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Synthetic Peptides That Antagonize the Angiotensin-Converting Enzyme-2 (ACE-2) Interaction with SARS-CoV-2 Receptor Binding Spike Protein
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  • Afsaneh Sadremomtaz
    Afsaneh Sadremomtaz
    XB20 Drug Design, Groningen Research Institute of Pharmacy, University of Groningen, 9700 AD Groningen, The Netherlands
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  • Zayana M. Al-Dahmani
    Zayana M. Al-Dahmani
    XB20 Drug Design, Groningen Research Institute of Pharmacy, University of Groningen, 9700 AD Groningen, The Netherlands
    Department of Medical Microbiology and Infection Prevention, University of Groningen, University Medical Center Groningen, 9700RB Groningen, The Netherlands
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  • Angel J. Ruiz-Moreno
    Angel J. Ruiz-Moreno
    XB20 Drug Design, Groningen Research Institute of Pharmacy, University of Groningen, 9700 AD Groningen, The Netherlands
    Departamento de Farmacología, Facultad de Medicina, Universidad Nacional Autónoma de Mexico (UNAM), Ciudad de Mexico 04510, Mexico
    Unidad Periférica de Investigación en Biomedicina Translacional, Facultad de Medicina, Universidad Nacional Autónoma de México (UNAM), Félix Cuevas 540, Ciudad de Mexico 03229, Mexico
    Doctorado en Ciencias Biomédicas, Universidad Nacional Autónoma de México (UNAM), Ciudad de Mexico 04510, Mexico
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  • Alessandra Monti
    Alessandra Monti
    Institute of Biostructures and Bioimaging (IBB)-CNR, Via Mezzocannone, 16, 80134 Napoli, Italy
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  • Chao Wang
    Chao Wang
    XB20 Drug Design, Groningen Research Institute of Pharmacy, University of Groningen, 9700 AD Groningen, The Netherlands
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  • Taha Azad
    Taha Azad
    Center for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, K1H 8L6 ON, Canada
    Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, K1H 8M5 ON, Canada
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  • John C. Bell
    John C. Bell
    Center for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, K1H 8L6 ON, Canada
    Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, K1H 8M5 ON, Canada
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  • Nunzianna Doti
    Nunzianna Doti
    Institute of Biostructures and Bioimaging (IBB)-CNR, Via Mezzocannone, 16, 80134 Napoli, Italy
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  • Marco A. Velasco-Velázquez
    Marco A. Velasco-Velázquez
    Departamento de Farmacología, Facultad de Medicina, Universidad Nacional Autónoma de Mexico (UNAM), Ciudad de Mexico 04510, Mexico
    Unidad Periférica de Investigación en Biomedicina Translacional, Facultad de Medicina, Universidad Nacional Autónoma de México (UNAM), Félix Cuevas 540, Ciudad de Mexico 03229, Mexico
    Doctorado en Ciencias Biomédicas, Universidad Nacional Autónoma de México (UNAM), Ciudad de Mexico 04510, Mexico
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    Orcidhttps://orcid.org/0000-0001-9717-0265
  • Debora de Jong
    Debora de Jong
    Department of Medical Microbiology and Infection Prevention, University of Groningen, University Medical Center Groningen, 9700RB Groningen, The Netherlands
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  • Jørgen de Jonge
    Jørgen de Jonge
    Centre for Infectious Disease Control, National Institute for Public Health and the Environment (RIVM), 3720BA Bilthoven, The Netherlands
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  • Jolanda Smit
    Jolanda Smit
    Department of Medical Microbiology and Infection Prevention, University of Groningen, University Medical Center Groningen, 9700RB Groningen, The Netherlands
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    Orcidhttps://orcid.org/0000-0001-6951-1448
  • Alexander Dömling
    Alexander Dömling
    XB20 Drug Design, Groningen Research Institute of Pharmacy, University of Groningen, 9700 AD Groningen, The Netherlands
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    Orcidhttps://orcid.org/0000-0002-9923-8873
  • Harry van Goor*
    Harry van Goor
    Department of Medical Microbiology and Infection Prevention, University of Groningen, University Medical Center Groningen, 9700RB Groningen, The Netherlands
    *Email: [email protected]
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  • Matthew R. Groves*
    Matthew R. Groves
    XB20 Drug Design, Groningen Research Institute of Pharmacy, University of Groningen, 9700 AD Groningen, The Netherlands
    *Email: [email protected]
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    Orcidhttps://orcid.org/0000-0001-9859-5177
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Journal of Medicinal Chemistry

Cite this: J. Med. Chem. 2022, 65, 4, 2836–2847
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https://doi.org/10.1021/acs.jmedchem.1c00477
Published July 30, 2021

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Abstract

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The SARS-CoV-2 viral spike protein S receptor-binding domain (S-RBD) binds ACE2 on host cells to initiate molecular events, resulting in intracellular release of the viral genome. Therefore, antagonists of this interaction could allow a modality for therapeutic intervention. Peptides can inhibit the S-RBD:ACE2 interaction by interacting with the protein–protein interface. In this study, protein contact atlas data and molecular dynamics simulations were used to locate interaction hotspots on the secondary structure elements α1, α2, α3, β3, and β4 of ACE2. We designed a library of discontinuous peptides based upon a combination of the hotspot interactions, which were synthesized and screened in a bioluminescence-based assay. The peptides demonstrated high efficacy in antagonizing the SARS-CoV-2 S-RBD:ACE2 interaction and were validated by microscale thermophoresis which demonstrated strong binding affinity (∼10 nM) of these peptides to S-RBD. We anticipate that such discontinuous peptides may hold the potential for an efficient therapeutic treatment for COVID-19.

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SPECIAL ISSUE

This article is part of the COVID-19 special issue.

Introduction

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To date, more than 100 coronaviruses have been discovered (https://www.who.int/emergencies/diseases/novel-coronavirus-2019/situation-reports/) and no targeted therapy yet exists for the current emergency of SARS-CoV-2 (COVID-19) infections. Scientists have applied many strategies against COVID-19, including assessing existing available antiviral drugs, (1) computationally screening for molecules, (2,3) designing compounds to block viral RNA synthesis/replication, (4−6) recognizing hotspot loops and residues to ligate the active axes of the virus by blocking binding to cognate human cell receptors, (7,8) using peptidomimetic reporters and identifying host specific receptors or enzymes to design specific drugs or vaccines, (9,10) targeting downstream host innate immune signaling pathways, (11) and performing computational genomic and pathological studies on different kinds of coronaviruses to design new drugs. (12−15)
There is a continuously evolving global effort to develop COVID-19 treatments or vaccines. Testing multiple approaches will improve the chance that a treatment is discovered. According to a WHO analysis of candidate COVID-19 vaccines, 64 are in clinical assessment (with 13 at phase 3) and 173 are in preclinical analyses. Phase 3 vaccine candidates include a variety of vaccine platforms: vector vaccines, mRNA-based vaccines, inactivated vaccines, and adjuvanted recombinant protein nanoparticles. (16−27)
The initial and critical route of entry of both SARS-CoV and SARS-CoV-2 viruses is the interaction between the viral S protein and ACE2 receptor. Therefore, impairing S-RBD binding to ACE2 has the potential to inhibit viral entry into human cells, presenting an opportunity for therapeutic intervention as a complement to vaccination strategies. While small molecules could disrupt the S-protein and ACE2 receptor interaction, they are suboptimal to target large protein–protein interactions (PPIs). (28−33) Antagonistic peptide drugs represent the best tool to inhibit the S-RBD:ACE2 interaction, as such peptides combine the best features of antibody approaches (ability to address a large and relatively featureless surface) and small-molecule approaches (improved pharmacokinetics, reduced immune response, ease of production, and cost of goods). (34−54)
The interface between S-RBD and ACE2 has been recognized as a potential area for antagonism to inhibit viral propagation, and peptides derived from ACE2 have been used successfully to block SARS-CoV-2 cell entry. (48) The concept of utilizing discontinued peptides in drug discovery, and especially to combat SARS-CoV cell entry, was initiated decades ago with the discovery of the P6 peptide (EEQAKTFLDKFNHEAEDLFYQSS-G-LGKGDFR). (48) This peptide is derived from a library of peptides based on the α1 helix of ACE2. The P6 peptide is artificially linked by glycine that keeps two separate segments of ACE2 in close proximity and shows antiviral activity (IC50 = 0.1 mM). (48) This finding indicated that a core of S-RBD interacts with same α1 helix of ACE2. This approach is supported by recent publications that have suggested ACE2-based peptides as strong candidates for optimization into therapeutics (34−37) and is a complementary approach to vaccine development as well as the identification of small-molecule-based therapies (novel or repurposed). The strength of the interaction between ACE2 and S-RBD has been determined by a number of authors, indicating binding affinities of 94 and 44 nM by isothermal titration calorimetry (ITC) and surface plasmon resonance (SPR), respectively. (49,50) These figures provide an estimate for the required strength of interaction between any peptides and their target molecules that could reasonably be expected to antagonize the ACE2–S-RBD interaction, and ACE2-based peptide inhibitors of SARS-CoV-2 (34−37) have recently been described. While this early stage of peptide inhibitor development showed great promise, only a few ACE-2-based peptides were proposed and screened, including SBP, a peptide that specifically binds S-RBD with micromolar affinity (1.3 μM) as assessed by biolayer interferometry. (34) A series of biosimilar peptides has recently been generated based on the N-terminal helix of human ACE2, which contains the majority of the residues at the binding interface, which displayed a high helical propensity. One of their most promising peptide-mimics (P10) blocked SARS-CoV-2 human pulmonary cell infection with an IC50 of 42 nM and 0.03 nM binding affinity (Kd), as assessed by biolayer interferometry. (36) A recent publication also reported that four stapled peptides show antiviral activity in HT1080/ACE2 cells (IC50 of 1.9 to 4.1 μM) and A549/ACE2 (IC50 of 2.2 to 2.8 μM). (37) The most promising of these peptides binds SARS-CoV-2 S-RBD with a Kd of 2.2 μM, as determined by SPR.
Additionally, a recent report describes the therapeutic effect of a tandem, lipidated peptide (1168-DISGINASWNIQKEIDRLNEVAKNLNESLIDLQEL-1203) from the heptad repeat (HRC) domain of SARS-CoV-2 in a ferret model. (39) This peptide has IC50 values of 303.1 nM in viral infection assays. However, the direct strength of interaction to the target S-RBD is unreported. (38) Further, a recently reported multiepitope peptide-based SARS-CoV-2 vaccine demonstrated high immunogenic response (IC50 of 2.4 μM and 9.0 μM for peptides 1 and 2, respectively). Finally, a defensin-like peptide P9R (NGAICWGPCPTAFRQIGNCGRFRVRCCRIR) displayed excellent activity against pH dependent viruses (IC50 of 0.26 nM). (40)
The availability of high-resolution structural information has facilitated this approach, by identifying the key interaction points between the two molecules of ACE2 and S-RBD (PDB: 6MOJ and 6M17). (51) However, the interaction strength of a single linear epitope of ACE2 is likely to be significantly inferior to that displayed by a composite peptide that is composed of disparate interaction epitopes. We have previously shown similar behavior in the design of a composite VEGF:VEGFR antagonistic peptide, that was shown to be competitive with an antibody-based approach in vitro and in vivo. (52−54) Similarly, the concatenation of disparate binding elements resulted in improved binding properties. This leads to the concept of a peptide-based therapeutic for the current SARS-CoV-2 outbreak, which would complement antibody-based approaches, but with the additional advantages of peptides over antibodies in terms of reduced cost-of-goods, immune response, ease of production, and improved pharmacokinetics. All of these issues are clearly of immense importance in developing therapeutics for the current outbreak.
In this paper, molecular docking and protein contact atlas (55−59) analysis revealed a number of interactions that are essential for the SARS-CoV-2 S-RBD:ACE2 interaction. Analyzing the S-RBD/ACE2 crystal structure (PDB ID: 6M0J and 6M17), and modeling the key interacting motifs of S-RBD with ACE2, we identified a number of hotspot loops distributed on the surface and thereby implicated as critical for virus entry into human cells. Analysis of this data resulted in a library of six peptides that we predicted would efficiently antagonize SARS-CoV-2 S-RBD:ACE2 interaction. This library was synthesized and assayed against an in vitro bioluminescence assay (60) to determine their inhibition of the SARS-CoV-2 S-RBD:ACE2 interaction. Our data below demonstrates that all six peptides were able to strongly compete for this interaction. While this approach clearly shows the efficacy of our peptides, we also performed microscale thermophoresis (MST) experiments to validate our proposed mode of inhibition, as well as to determine in vitro peptide binding affinities to purified SARS-CoV-2 S-RBD. The MST data indicates that a number of the peptides have binding affinities in the low nanomolar range with peptides 5 and 6 displaying affinities of 13 and 45 nM, respectively, which is competitive with literature reported values of 0.03 (36) and 1300 nM (34) binding affinity for P10 and SBP1 (ACE2 antagonist peptide), respectively.
In summary, this paper provides a clear indication that a composite peptide of ACE2, composed of loop elements that support the central interaction motif of its with S-RBD, can efficiently antagonize this essential interaction in vitro and provide the basis for further discovery of a COVID-19 therapeutic.

Results and Discussion

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Molecular Docking and Computational Modeling of ACE2:S-RBD Antagonistic Peptides

To identify key SARS-CoV-2 S-RBD:ACE2 interaction residues, protein–protein docking was performed using HADDOCK (61) and binding interfaces were predicted using protein contact atlas. (59) Additionally, we performed a structural analysis aiming to identify the S-RBD amino acids which energetically favor contacts with the ACE2 receptor by stabilizing a number of important interactions (Tables 1 and 2). The molecular interaction profile allowed us to identify the most frequent contacts between the peptides and S-RBD, suggesting these peptides may block the SARS-CoV-2 S-RBD:ACE2 axis by directly binding and inducing conformational changes in SARS-CoV-2 S-RBD (Figures 1 and 2).
Table 1. Amino Acid Sequences of ACE2-Antagonist Peptidesa
  m/z (monoisotopic)  
entrysequencetheorexptlKd (nM)IC50 (nM)
peptide 1H-IEEQAKTFLDKFQHEVEEIYWQS-NH22895.3972895.477106 ± 111 ± 1
peptide 2H-QDKHEEDYQMYNKGDKED-NH22269.9442270.011102 ± 618 ± 2
peptide 3H -DKFNHEAEDLFYQSSLASWNYNT-NH22777.2252777.304245 ± 36 ± 4
peptide 4H-IDENARSYIDKFQHDAEEMWYQ-NH22786.2282786.308541 ± 532 ± 2
peptide 5H-IYALLENAEDYNLVN-NH21751.8621751.92013 ± 19 ± 4
peptide 6H-SRDKHEEHEKENDRGQ-NH21991.9051991.96646 ± 510 ± 5
a

Theoretical and experimental molecular weight, half-maximal inhibitory concentration (IC50) using a luciferase assay and binding affinities of SARS-CoV-2:ACE2-antagonist peptides (determined using) MST are also shown. Peptides were synthesized on solid phase using the F-moc strategy, have a free N-terminus, and are amidated at the C-terminus.

Figure 1

Figure 1. Interaction of ACE2 with S-RBD. (a) Surface representation of the complex between the receptor binding (S-RBD) domain of SARS-CoV-2 Spike protein (yellow) and the human ACE2 receptor (pink) (PDB ID: 6M0J). The portion of the ACE2 domain including main interacting residues of helices α1 (I21, Q24, T27, F28, D30, K31, H34, E35, E37, D38, Y41, Q42), α2 (L79, M82, Y83), and α3 (N330, K419, D430, E431) and β sheets β3 and β4 (K353, G354, D355, and R357) are drawn in green. (b) A closer view displays the interacting residues at the interface site. Figure created by PyMol (Molecular Graphics System, ver. 1.2r3pre, Schrödinger, LLC).

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Figure 2

Figure 2. Stick representation of residues involved in the interprotomer interaction of S-RBD. (a) Side view of the surface representation of the interactions within ACE2 and S-RRBD (PDB ID: 6M0J). (b) Residues involved in the subunit interaction are shown in green (cartoon transparency is set to 40%). Four contact regions are located in the α1, α2and α3 helices and in β3 and β4 of ACE2 and S-RBD. Figure created by PyMol (Molecular Graphics System, ver. 1.2r3pre, Schrödinger, LLC).

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Table 2. Table of Energetic Calculations Using HADDOCKa
entryelectrostatic energy score (arbitrary units of energy)van der Waals energy score (arbitrary units of energy)scoreburied surface area (A•2)effect
peptide 1–284.989 ± 2.3–113.23 ± 1.1–94.364 ± 7.2927.565 ± 32B
peptide 2–386.163 ± 1.7–127.31 ± 2.2–104.789 ± 4.31024.23 ± 21C
peptide 3–272.940 ± 2.4–111.43 ± 0.17–93.334 ± 9.6995.967 ± 34B
peptide 4–265.347 ± 1.1–105.61 ± 0.9–87.56 ± 3.51021.25 ± 29B
peptide 5–388.163 ± 4.2–190.20 ± 1.4–155.53 ± 9.21123.57 ± 37D
peptide 6–383.163 ± 3.3–187.36 ± 1.9–143.034 ± 10.131017.77 ± 41D
a

Effect; The experimentally determined effect on interaction of ACE2 with S-RBD. A: No effect on interaction with S-RBD. B: Slightly inhibits interaction with S-RBD. C: Strongly inhibits interaction with S-RBD. D: Abolishes interaction with S-RBD.

Structural reports identified key 14 residues as important in the interaction of SARS-CoV S-RBD with ACE2 (62) and revealed critical amino acid residues at the contact interface between S-RBD and full-length human ACE2 receptor. Analysis of 144 SARS-CoV-2 genome sequences available from GISAID (Global Initiative on Sharing All Influenza Data) (63) indicated that 8 of these 14 amino acids are strictly conserved (Table S1).
We first analyzed the interacting residues at the ACE2 and S-RBD interface using the crystal structures of ACE2 and S-RBD of SARS-CoV-2 (PDB: 6M0J and 6M17) and PDBePISA. (64) Fifteen residues of 23 residues (21–43) located on the α1 helix of ACE2 interact with S-RBD. These residues are clearly located in the crystal structure and include Q24, T27, D30, K31, H34, E35, E37, D38, Y41, and Q42 from helix α1, one residue (M82) from helix α2, and residues K353, G354, D355, and R357 from the β3-β4 linker. Most of the interacting residues are located in α1 (Figures 1 and 2). Using the results from protein–protein molecular docking and the structural analysis, we assembled peptide 1, peptide 3, and peptide 4 from helix α1 alone (Table 1). The design strategy of peptide 2 is as a discontinuous peptide that includes some critical interacting amino acids from α1, α2, and α3 (330, 419, 430, and 431) and some key amino acids from residues between β3 and β4 (353 to 355), as shown in Figures 1, 2b and S1. However, a number of amino acids were identified as passenger residues and replaced with appropriate amino acids to preserve the binding energy (Figures 1, 2, and S1). Peptide 5 was again designed around helix α1, but to additionally include main interacting amino acids from helix α2 (V59, N63, D67, A71, E75, L79, and Y83). Finally, we designed a highly discontinuous peptide (peptide 6) including residues from α1, α2, and α3 helices and β4 that are known to bind to S-RBD (Figures 1, 2b, and S1b; Table S2).
We performed molecular docking experiments with the peptides and a model of SARS-CoV-2 S-RBD to characterize the binding of the designed peptides. All docking experiments showed that the peptides bind at the S-RBD surface in a manner similar to that of the α1 helix of ACE2. Furthermore, the analysis of binding by explicit solvent MD indicates that all peptides remained bound to S-RDB over the whole simulation. Importantly, the pairwise backbone RMSD analysis of four of the peptides showed a distinct profile to that generated by apo-S-RBD (Figure 3a). Binding of peptides 1, 2, 5, and 6 decreases the RMSD of the S-RBD backbone when compared with the apo structure (Figure 3). This induced transition might lead to a less flexible conformation of the protein, modulating the active state of the S-RBD protein and thus improving the affinity and the residence time of the peptides. The thermodynamic and kinetics of this conformational transition of ligand–receptor systems has been described previously. (65,66)

Figure 3

Figure 3. (a) Heat maps representing the pairwise backbone RMSD matrix of SARS-CoV-2 S-RBD protein calculated for the backbone along 50 ns of MD simulation from systems including peptides with stable binding to S-RBD. The unliganded protein (apo-RBD) is included for comparison. The simulation corresponding to apo-RBD displays a higher RMSD in comparison with the matrices originated for peptides 1, 2, 5, and 6. Indicating a less flexible conformation of S-RBD. (b) The unliganded protein (ACE2:S-RBD) is included for comparison

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Additionally, a carbon alpha RMSF analysis of S-RBD (Figure 4) showed that most of peptides modified the fluctuations occurring in apo-S-RBD (Figure 4a). In particular, peptides 1–5 decreased the fluctuations among most of the residues. Notably, a considerable increase in RMSF values was observed on residues 469–488, comprising a flexible loop in proximity to the binding site of the peptides (Figure 4). This same loop has been described as containing key contacts for the interaction with the human ACE2 protein. (35,48) Moreover, we observed an overall RMSF change distribution on the S-RBD structure (Figure 4b and c). Although all peptides remain bound to S-RBD, peptide 6 displayed a nonunique binding mode. In the simulations, this peptide leaves the initial binding site and binds into different regions of S-RBD, causing a notable increment in S-RBD fluctuation (Figure 4c). Conversely, peptides 1, 4, and 5 are suggested to be the most stable binders, since they maintained a similar binding mode throughout the MD simulation (Figure 4c). Moreover, the molecular interactions profiles from MD indicated that peptides 1, 2, 4, and 5 formed high frequency interactions with the same residues where the helices α1 and α2 of ACE2 bind (Figure S1). On the other hand, peptide 3 showed lower frequency of interactions (Figure S1). Moreover, peptide 3 also showed a more variable binding mode (Figure 4c). Finally, peptide 6 showed a nonunique binding mode by exploring other regions of S-RBD (Figure 4c) as a consequence, the molecular interaction profile indicated the formation of interactions with several residues of the S-RBD protein (Figure S1a) including those of the SARS-CoV-2 S-RBD:ACE2 interface (Figure S1).

Figure 4

Figure 4. α-Carbon RMSF analysis for the peptide-S-RBD systems. (a) α-Carbon RMSF profiles of all studied peptides, apo-S-RBD, and ACE2 are presented for comparison. (b) RMSF structural representation of apo-S-RBD and ACE2:S-RBD. (c) structural representation of peptide:S-RBD complexes including the binding of the peptides across 10 representative snapshots. Normalized scale for peptides 1–5; peptide 6 is presented with its own scale.

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Interestingly, as shown in Table 2, peptides 1, 3, and 4 are closest in binding energies, likely as they are structurally similar and derived from helix α1 alone. Peptides 2, 5, and 6 have higher binding strength than the α-1 helix alone, in which the van der Waals and electrostatic interactions make a significant contribution (Table 2 and Figure S2). Taken together, these data suggest that the six designed peptides could bind SARS-CoV-2 S-RBD and induce a conformational change. Additionally, the MD interaction analysis suggested that the designed peptides would bind with a high affinity to S-RBD, with the exception of peptide 3. As a consequence, we decided to synthesize and evaluate their ability to antagonize the S-RBD:ACE2 interaction and their binding to a recombinant SARS-CoV-2 S-RBD (Figure S3).

Biophysical Characterization of Peptides of ACE2-Antagonist Peptides

Preliminary binding experiments between SARS-CoV-2 S-RBD protein domain and ACE2-antagonist peptides dissolved in PBS did not provide reproducible results (data not shown). We hypothesized that this is a result of poor aqueous solubility and/or aggregation phenomena of peptides in our experimental conditions. In line with this hypothesis, sequence analysis using the AGGRESCAN server (http://biocomp.chem.uw.edu.pl/A3D/) (67) suggested that all peptides, apart from peptides 4 and 6, show a propensity for self-aggregation (Figure S4).
Therefore, to identify experimental conditions for further assays, we performed a biophysical characterization of peptides. First, we comparatively assessed the solubility of peptides in PBS with and without additives such as Tween 20 and 1% (w/v) PEG8000, starting from the same stock solutions prepared in DMSO. We determined the difference between the experimental and the theoretical values as percentage of the theoretical values (% Error), for each solution tested. As reported in Table S3, a significant discrepancy between the experimental and theoretical values was observed in peptides dissolved in PBS compared to those dissolved in PBST, 1% (w/v) PEG8000. As long as the analyzed solutions in PBS and PBST, 1% (w/v) PEG8000 were prepared from the same stocks, Tween and PEG8000 in PBS significantly increase the solubility of the peptides in solution. In our attempt to compare the solubility of peptides in PBST, 1% (w/v) PEG8000 used in this study, with respect to the PBS in the working concentrations (low micromolar range), we performed intrinsic fluorescence analysis following aromatic residues (Figure S5). Accordingly, we scanned the fluorescence emission spectra from 300 to 500 nm for peptides containing aromatic residues (Table 1).
As shown in Figure S5, the fluorescence emission increases linearly with peptide concentration for most peptides dissolved in PBST, 1% (w/v) PEG8000 and in PBS, indicating that peptides are soluble in the range of concentration tested. Differently, peptide 2 did not show a dose-dependent increase of fluorescence emission when dissolved in PBS compared to that dissolved in PBST, 1% (w/v) PEG8000. Indeed, a significant quenching of fluorescence emission is observed at the highest concentration tested (12.5 and 25 μM), suggesting that precipitation/aggregation phenomena or conformational changes occur in PBS. Of note, in all peptides tested, a quenching of fluorescence emission, primarily at the highest concentrations tested, has been observed in peptides dissolved in PBS compared to those dissolved in PBST, 1% (w/v) PEG8000 (Figure S6), suggesting different conformational behaviors of peptides in the two buffers used.
In this framework, the putative conformational changes of peptides in the two buffers has been evaluated using CD spectroscopy. The spectra of all peptides appeared disordered in PBS buffer, characterized with a strong peak minimum at 198 nm and a negative value at 190 nm, and showed more ordered structures, as detected by the appearance of a positive band at 190 nm and by the shift of the minimum from 198 to 205 nm, when dissolved in PBST, 1% (w/v) PEG8000 (Figure S7), suggesting that the presence of Tween and PEG8000 in the PBS better stabilizes the conformation of peptides.
Finally, the conformational behavior of peptides in the two buffers was further investigated by performing a comparative analysis with analytical size-exclusion chromatography (SEC) (see Experimental Section for details). Under the same experimental conditions, all peptides eluted as a single peak from the SEC column as observed in Figure S8. However, apart from peptide 1, all peptides showed a delayed retention time (Rt) when dissolved in PBS compared to those dissolved in PBST, 1% (w/v) PEG8000. Considering the apparent molecular weights of the synthetic peptides, calculated by a calibration curve, and their theoretical molecular weights, the number of the units of all peptides span in the range of 0.9–1.4 for peptides dissolved in PBST, 1% (w/v) PEG8000 and 0.3–0.9 for those dissolved in PBS (Figure S8). These data show that while all peptides are monomers in both buffers, they exhibit a more compact conformation in PBS with respect to that in PBST 1% (w/v) PEG8000. Conversely, peptide 1 showed a more open conformation in PBS with respect to that in PBST 1% (w/v) PEG8000. However, the elution peak in PBST, 1% (w/v) PEG8000 is very wide suggesting the presence of several conformation in solution.
Altogether these data show that no oligomerization are detectable in PBS or PBST, 1% (w/v) PEG8000. However, the presence of two surfactants increases the aqueous solubility of peptides and provides greater stabilization of the conformation of the peptides in solution. For these reasons, binding studies were performed using PBST, 1% (w/v) PEG8000 to solubilize the peptides.

Synthetic Peptides Efficiently Block the Interaction of ACE2 with S-RBD

The various ACE2 antagonist peptides identified above were synthesized and assessed for their ability to inhibit the S-RBD interaction with ACE2 using a luciferase assay (Figure 5a). Taha et al. (60) provides a novel bioluminescence-based sensor reporter system, the reassembly of SmBiT and LgBiT into NanoBiT when S-RBD and ACE2 interact, to probe antagonism of the protein–protein interaction. This sensitive yet robust assay, developed for the discovery of neutralizing antibodies, allowed us to rapidly test peptide-based antagonism of the SARS-CoV-2 S-RBD:ACE2 interaction. Initially, we measured toxicity and inhibition of infection at nine concentrations (0–25 μM) of peptides, performed in triplicate (Figure 5a). We then used ACE2-antagonistic peptides to determine whether these peptides could disrupt the SARS-CoV-2 S-RBD:ACE2 interaction in a cell-based system. The reported half-maximal inhibitory concentration (IC50) of our peptides against the SARS-CoV-2 S-RBD:ACE2 interaction demonstrates dose-dependent inhibition, with measured IC50s of 11 ± 5, 18 ± 2, 6 ± 3, 32 ± 2, 9 ± 4, and 10 ± 3 nM against peptides 1–6, respectively (Table 1 and Figure 5a). At the highest concentrations used (25 μM), all peptides completely inhibited S-RBD binding to ACE2. At a concentration of 0.39 μM, peptides 2 and 4 exhibited up to ∼95% inhibition, and peptides 1, 3, 5, and 6 exhibited statistically significant inhibition of S-RBD binding at concentrations as low as 0.09 μM (Figure 5a).

Figure 5

Figure 5. (a) Binding analysis for the interaction between S-RBD and ACE2. (a) Luciferase-based assay. 293T cells were transfected with the ACE2 or S-RBD expression constructs. 48 h post-transfection, and luciferase assays were performed on 20 μg total protein from cell lysates using FMZ as a substrate (n = 3, mean ± SD; one-way ANOVA, ***p < 0.005 relative to smBiT-ACE2 alone, Dunnett’s correction for multiple comparisons). (b) MST analysis of peptide 1–6 binding to recombinant S-RBD. The concentration of S-RBD is kept constant at 50 nM, while the ligand concentration varies from 12.5 μM to 0.19 nM. Serial titrations result in measurable changes in the fluorescence signal within a temperature gradient that can be used to calculate the dissociation constant (Kd). The curve is shown as ΔFnorm (change of Fnorm with respect to the zero-ligand concentration) against S-RBD concentration on a log scale.

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Synthetic Peptides Bind to Purified S-RBD with Nanomolar Affinity

Microscale thermophoresis (MST) of the interaction of purified S-RBD with the six designed peptides was performed on a NanoTemper Monolith NT.115 (Nano Temper Technologies, Germany) and the results are shown in Figure 5b. To perform these experiments, pure S-RBD protein was labeled and incubated with a peptide concentration series (12.5–0.00019 μM) in PBS-Tween (0.01%) + 1% (w/v) PEG8000 (w/v). The addition of Tween and PEG8000 was necessary, as previous experiments in the absence of these reagents resulted in a high degree of aggregation of the peptide in the MST experiments. Triplicates of the thermophoretic progress curves are reported as the median of Kd posterior distribution for peptide 1 to peptide 6, showing values of 106 ± 1, 102 ± 6, 245 ± 3, 542 ± 5, 13 ± 1 and 46 ± 5 nM, respectively. Overall, all six peptides showed a sigmoid binding curve with Kd in the low nanomolar range, which indicate a strong binding of these peptides to the protein in a short incubation time (5 min). Results shown are mean ± SD of 3 measurements and are in close correlation with those of the luciferase assay (Figure 5b), in which peptides 5 and 6 also demonstrated the strongest antagonism (Figure 5b). Given the affinity of SARS-CoV-2 S-RBD to ACE2 has been reported as 44.2 (49) and 94 nM (50) by SPR and ITC, respectively, these peptides clearly offer an opportunity to effectively inhibit viral cell entry in an in vivo settling.
In summary, the MST binding affinity experiments demonstrated that all peptides bind to SARS-CoV-2 S-RBD, and our MD data suggest that the noncontinuous design of peptide 6 might contribute to a nonunique binding mode allowing this peptide to bind similarly to helix1 and helix 2 of ACE2, but also including other proximal areas of S-RBD with a considerable enhancement of the binding affinity.

Conclusion

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During an outbreak, conventional small molecule drug discovery (68−70) is perhaps not the most efficient option, as it cannot easily provide a sufficiently rapid solution. Several advantages over conventional small molecule drugs have been presented with peptide-based therapeutics, including elevated specificity and synthesis savings in both cost and time. (69,70) While this increased specificity is also accomplished by monoclonal antibodies, (45,60) they are expensive and labor-intensive to synthesize. There has also been some controversy over antibody mediated viral entry, which may lead to acute disease. Several approaches, such as drug repurposing, vaccination, and immunotherapy, represent reasonable alternatives. However, immunotherapy and vaccination approaches utilize peptide targets, and molecular dynamic simulations on the available X-ray crystal structure of the SARS-CoV-2 ACE2/S-RBD complex provided a straightforward way to identify potential peptide-based therapeutics. (69)
Several groups have reported peptides that recognize either ACE2 or SARS-CoV-2 S-RBD and inhibit virus from entering human cells in vitro and in vivo. Four SARS-BLOCK synthetic peptides were shown to inhibit SARS-CoV-2 spike protein-mediated infection of human ACE2-expressing cells LPDPLKPTKRSFIEDLLFNKVTLADAGFMKQYG (Kd = 2 ± 1 μM), ASANLAATKMSECVLGQSKRVDFCGKGYH (Kd = 5 ± 2 μM), QILPDPSKPSKRSFIEDLLFNKVTLADAGFIK, ASANLAATKMSECVLGQSKRVDFCGKGY (Kd = 4 ± 2 μM), and ASANLAATKMSECVLGQSKRVDFCGKGY (Kd = 2 ± 2 μM). (44) To date, the most promising candidates of N-terminal ACE2 α1 helix-based peptides have been reported by a 27-mer peptide (aa 19–45) (36) and a 23-mer peptide (aa 21–43), (34) termed P10 and SBP1, respectively, which were shown to bind to S-RBD with a Kd of 0.03 nM and 1.3 μM, respectively, as assessed by biolayer interferometry. However, SBP1 binds to S-RBD which was expressed in insect cells, and the results were not reproduced with human and other insect-derived RBDs (provided from commercial sources). (34) This suggests that either the α1 helix of ACE2 is not sufficient to bind S-RBD or it loses its helical structure, and thereby its ability to bind S-RBD, in solution. This finding is in good agreement with recent reports, (34−37) and our luciferase and MST results for peptides 1–4 (Figure 5) have demonstrated that α1 alone might not be sufficiently stable to provide a sufficiently strong interaction. In accordance with this finding, Yanxiao et al. (35) reported initial computational findings that indicated an interaction between α1 and α2-helices may help retain their bent shape to match to the binding surface of SARS-COV-2 S-RBD, providing a more complete coverage of the S-RBD surface than the α1 helix alone. To provide additional confidence in the design of our peptide candidates, we compared the results of peptide 5 with peptide 1 (Figure 5). This follow-up comparison demonstrated that a candidate containing contributions from both α1 and α2 helices showed a more than 7-fold improvement in binding affinity to S-RBD, compared with other α1-helix-based peptides (peptide 1). Peptide 6 additionally comprises residues from three helices and β4 and shows similar levels of activity in the competition assay. It also demonstrated an ∼2-fold improvement in affinity over peptide 1 in binding affinity (Figure 5b). In summary, this indicates that helices α1 and α2 are likely closely packed together in the interaction of peptide 6 with SARS-CoV-2 S-RBD (Figures 1b and 2b), stabilizing each other to preserve structure as well as function.
Indeed, given the strong performance of our library of peptides with all ACE2- based peptides in the in vitro studies (12.9 and 45.9 nM for peptides 5 and 6, respectively), we believe that our peptides could provide a strong option for further drug development. However, our peptides derived from ACE2 are currently physiologically inactive as initial experiments on viral inhibition assays were unsuccessful (Table S3). Due to this lack of activity and the need to use surfactants (PEG8000 and Tween20), which are known to be cytotoxic in cell-based assays, we have also not performed cytotoxicity assays. Analysis of the solution properties of the peptides in this study clearly demonstrates a variation in peptide solubility and overall conformation in the absence or presence of these surfactants (Supporting Information), and modifications will need to be made to our peptides to translate the measured in vitro activity and binding affinity into activity in cell-based assays. However, similar difficulties have been previously reported in the design of S-RBD:ACE2 antagonistic peptides, (71−73) which were addressed by creating a tandem peptide, linked by a cholesterol moiety. (39) These experiments are currently underway and the results will be reported in a subsequent manuscript.
We believe that our data provides the first direct proof that, while the ACE2 α1 helix is an essential component for binding S-RBD, other loop regions such as helices α2, α3 and sheets β3, β4 of ACE2 also contribute significantly to the binding of SARS-CoV-2 S-RBD. We utilized a library of discontinues peptides to target S-RBD specifically and inhibit interaction of ACE2 with ACE2-S-RBD. Our study also further highlights the potential of a discontinuous peptide-based strategy in identifying antiviral drugs to target new mutations of S-RBD interactions which will undoubtedly offer an approach against future pandemics.

Experimental Section

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Protein-Peptide Docking

The crystal structure of the S-RBD-ACE2 (PDB ID: 6M0J) complex was retrieved from the Protein Data Bank (https://www.rcsb.org/) and used as the starting point for the docking studies. Molecular docking was performed using the HADDOCK 2.4 (61) server. The docking results were analyzed using the Chimera (74) and DS Visualizer programs. The results obtained were analyzed for binding energies and peptide conformations in the S-RBD binding interface. To identify hot-spot residues, we used Protein Contact Atlas (https://www.mrc-lmb.cam.ac.uk/rajini/index.html). (59) Briefly, we used a Chord Plot which shows the interactions between pairs of secondary structural elements (Figures 1 and 2), the adjacency matrix which reveals specific residue–residue interactions and represents the number of atomic contacts between them, an Asteroid Plot which shows the neighborhood of a particular residue or ligand, network statistics (Scatter Plot Matrix) which shows the network metrics corresponding to each residue (Closeness), statistics table that provides the degree, betweenness, and closeness centrality measures and solvated area of the selected residues), and the network view, in which interactions are represented as edges, with the edge thickness signifying the number of atoms that form contacts between the two residues).

Molecular Dynamics

MD simulations were performed using Gromacs 5.0.4. (55) The six designed peptides and S-RBD protein (6M0J) were parametrized using the CHARMM36 force field through the CHARMM-GUI (http://www.charmm-gui.org/). (56) For each peptide:S-RBD complex, the system was constructed by adding TIP3P water molecules, neutralizing ions, and establishing periodic boundary conditions (PBC) by using the multicomponent assembler of the CHARMM-GUI. Before production, the systems were minimized and then equilibrated under an NVT assembly. During the production phase, an NPT assembly was performed at 310.15 K for 50 ns saving velocities, and positions every 10 ps, and energy every 2 ps. Analysis of peptide-target interactions was computed by a python tailor-made script (https://github.com/AngelRuizMoreno/Scripts_Notebooks/blob/master/Scripts/plipMD_peptide_V1.1.py) using MDAnalysis (65) and PLIP. (66)

Free Energy Calculations

Full-length trajectories were employed for free energy calculations using the molecular mechanics energies combined with the Poisson–Boltzmann surface area continuum solvation (MM/PBSA) (68) by the g_mmpbsa v1.6 package. (69) Computation of the potential energy in vacuum, polar solvation energy, and nonpolar solvation energy were performed to calculate the average binding energy.

Peptide Synthesis and Characterization

Protected amino acids, coupling agents (HATU, Oxyma) used for peptide synthesis were purchased from Sigma-Aldrich (Milan, Italy) and Fmoc-Rink Amide MBHA LL resin was purchased from Novabiochem (Milan, Italy). Synthesis products, including acetonitrile (CH3CN), dimethylformamide (DMF), N,N′-diisopropylcarbodiimide (DIC), tri-isopropylsilane (TIS), trifluoroacetic acid (TFA), sym-collidine, diethyl-ether, and diisopropylethylamine (DIPEA), piperidine, were from Sigma-Aldrich (Milan, Italy). Peptides were assembled in the solid phase (Rink-Amide LL resin) with a substitution of 0.40 mmol/g, using a standard Fmoc peptide protocol with Oxyma-DIC and HATU-collidine as coupling reagents, as previously reported. (75) The cleavage of peptides from the solid support was performed by treatment with a TFA/TIS/H2O (95:2.5:2.5, v/v/v) mixture for 3 h at room temperature. Crude peptides were precipitated in cold diethyl-ether, dissolved in a H2O/CH3CN (75:25, v/v) mixture and lyophilized. Purifications were performed at 15 mL/min using a Jupiter C18 (5 μm, 300 Å, 150 × 21.2 mm ID) column applying a linear gradient of 0.1% TFA in CH3CN from 1% to 80% over 15 min, and monitoring the absorbance at 210 nm.
ESI-TOF-MS analyses of crude and purified peptides were performed with an Agilent 1290 Infinity LC System coupled to an Agilent 6230 time-of-flight (TOF) LC/MS System (Agilent Technologies, Cernusco Sul Naviglio, Italy). The liquid chromatograph Agilent 1290 LC module was coupled with a photodiode array detector (PDA) and a 6230 time-of-flight MS detector, along with a binary solvent pump degasser, column heater and autosampler. The characterizations were performed at 0.2 mL/min using a XBridge C18 column (5 μm, 50 × 2,1 mm ID) applying a linear gradient of 0.1% TFA in CH3CN from 1% to 80% over 10 min, and monitoring the absorbance at 210 nm. The relative purity of peptides was calculated as the ratio of peak area of the target peptide and the sum of areas of all detected peaks from the UV chromatograms. The purity of all peptides is more than 95% (Figure S3).

Determination of Peptide Concentrations

Peptide concentrations have been determined according to the Beer–Lambert law: A = εlc, where A is the absorbace at 280 nm, ε is the molar absorption coefficient, and l is the cell path length, by using the Thermo Scientific NanoDrop 2000/2000c spectrophotometer (PerkinElmer, Monza Italy). The ε values at 280 nm have been calculated according to the equation: ε280 = (5500nTrp) + (1490nTyr) + (125nS–S), where the numbers are the molar absorbances for tryptophan (Trp), tyrosine (Tyr), and cystine (i.e., the disulfide bond, S–S), and nTrp = number of Trp residues, nTyr = number of Tyr residuels, and nS–S = number of disulfide bonds. (76) The concentration of peptide A6, lacking of aromatic residues, has been calculated via the Scopus Method, monitoring the absorbance at 205 nm. (77)

Intrinsic Fluorescence Analysis

Measurements of the intrinsic fluorescence emission in solution of peptides were performed on a Jasco model FP-750 spectrofluorophotometer in a 1.0 cm path length quartz cell. Peptides were dissolved in DMSO to obtain stock solutions at 1.0 mM. Working solutions (3.125, 6.25, 12.5, and 25 μM) were subsequently prepared starting from fresh solutions at 25 μM obtained from dilutions with PBS or PBST-1% (w/v) PEG8000 by the stocks of each peptide. After the dilution, all samples appeared clear, and the fluorescence emission was recorded in the 300–500 range upon excitation at 280 and 295 nm for peptides containing tyrosine and tryptophan, respectively. Each spectrum is the average of three scans corrected by subtraction of appropriate blank.

Circular Dichroism (CD) Measurements

Far-UV (190–260 nm) CD spectra were recorded on a Jasco J-715 spectropolarimeter, equipped with a PTC-423S/15 Peltier temperature controller, in a 0.1 cm path-length quartz cell, at 25 °C, as previously reported in the literature. Peptides were dissolved in 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) to obtain stock solutions at 1.0 mM and therefore diluted in PBS and PBST, 1% (w/v) PEG8000 at final concentration of 25 μM with 2.5% HFIP. Each spectrum is the average of three scans corrected by subtraction of appropriate blank. Intensities were expressed as mean residue ellipticity, the molar ellipticity per mean residue [θ] × (deg cm2 dmol–1), obtained from the relation: [θ]222 = [θ]obs (mrw)/(10cl), where [θ]obs is the observed ellipticity in degree, “mrw” is the mean residue molecular weight of the protein, c is the protein concentration (g/mL), and l is the optical path length of the cell in cm.

Size-Exclusion Chromatography Experiments

Size-exclusion chromatography experiments were performed using an AKTA FPLC system (GE HEALTHCARE). Samples at about 10 mg/mL in DMSO were diluted in PBS and PBST, 1% (w/v) PEG8000 at a final concentration of 0.5 mg/mL, and 500 μL was loaded onto a BioSep-SEC-s2000 column 300 × 7.8 cm ID (Phenomenex), equilibrated with PBS at pH 7.0 at a flow rate of 0.5 mL/min. Chicken ovalbumin (44000 Da), myoglobin (16 900 Da), ribonuclease (13700 Da) and an unrelated peptide (ND, 2800 Da) were used as MW calibrants.

Plasmid Construction

Biosensors were cloned into the BamHI/NotI sites of pcDNA3.1 to generate mammalian expression constructs.

Cell Culture

293T (ATCC CRL-3216) were cultured in Dulbecco’s modified Eagle’s medium (Sigma) containing 10% FBS, and 1% penicillin/streptomycin (Invitrogen). (47)

In Vitro NanoLuc Assay

293T cells (3 × 105 cells) were plated in 12-well plates in triplicate 24 h before transfection. An amount of 500 ng of the biosensor constructs was transfected using PolyJet transfection reagent (SignaGen Laboratories). After 48 h, supernatant or cells were collected. Cells were lysed using passive lysis buffer (Promega), and NanoLuc luciferase assays were performed using one of two substrates: furimazine, FMZ(Nano-Glo Cell Reagent, Promega) or native coelenterazine, CTZ (3.33 uM final concentration) (Nanolight Technologies – Prolume Ltd., Pinetop, AZ, USA). Synergy Microplate Reader (BioTek, Winooski, VT, USA) was used to measure luminescence. Results are presented as RLU (Relative Luminescence Unit) normalized to control. The data presented are the mean of three independent experiments. (47)

Microscale Thermophoresis (MST)

The binding affinity of peptide to its cognate receptor was measured by Microscale thermophoresis (MST) on a Nanotemper Monolith NT.115 instrument (Nanotemper Technologies GmbH). Commercial S-RBD (RBD, FC Tag, 40592-v05H) was freshly labeled with the Monolith Lys-Tag RED-tris-NTA labeling dye according to the supplied protocol (Nanotemper Technologies, GmbH). The labeled protein was concentrated using a PES centrifugation filter (3 kDa cutoff; VWR). Measurements were done in MST buffer (50 mM Tris, 250 mM NaCl, pH = 7) in standard capillaries (K002; Nanotemper Technologies GmbH). The final concentrations of either labeled protein in the assay were 50 nM. The ligands (ACE2 peptides) were titrated in 1:1 dilution following manufacturer’s recommendations and starting from 12.5 uM. All binding reactions were incubated for 5 min on ice followed by centrifugation at 20 000g before loading into capillaries. Then, samples were loaded into standard glass capillaries (Monolith NTCapillaries, Nano Temper Technologies) and the MST analysis was performed (settings for the light-emitting diode and infrared laser were 80%). All measurements were performed in triplicate using automatically assigned 20% LED and 50% MST power; Laser On-time was 30 s and Laser Off time was 5 s.

Statistical Analysis

All graphs and statistical analyses were generated using Excel or GraphPad Prism ver. 8. Means of two groups were compared using two-tailed unpaired Student’s t test. Means of more than two groups were compared by one-way ANOVA with Dunnett’s or Tukey’s multiple comparisons correction. Alpha levels for all tests were 0.05, with a 95% confidence interval. Error was calculated as the standard deviation (SD). Measurements were taken from distinct samples. For all analyses, *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001; n.s. = not significant. Data was reproduced by two different operators.

Supporting Information

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The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.jmedchem.1c00477.

  • Additional figures illustrating molecular interaction from MD analysis of designed peptides and S-RBD, binding free energy of ACE2 derived peptides in complexes of S-RBD (binding energies of ACE2:S-RBD included for comparison), peptide LC-MS characterization, details of changes in hot spot area plot caused by aggregation of peptides, variation of fluorescence peak intensity with increasing concentration of peptides, CD spectra of peptides, overlay of emission spectra of samples dissolved in PBS and PBST, 1% (w/v) PEG8000 at 25 μM in 2.5% DMSO, and SEC of peptides; additional tables detailing key interactions between S-RBD and ACE2 identified using PiPreD, peptide sequences including replacement of some residues for improved targeting of S-RBD, analysis of data collected for the calculation of concentration of peptides in PBS and PBST, 1% (w/v) PEG8000 by UV spectroscopy analysis, theoretical, apparent molecular weight, and Rt values of ACE2-antagonist peptides as determined by SEC analysis, and dose–response results of the antiviral activity of peptides in a SARS-CoV-2 infection inhibition assay performed in VERO-E6 cells (PDF)

Terms & Conditions

Most electronic Supporting Information files are available without a subscription to ACS Web Editions. Such files may be downloaded by article for research use (if there is a public use license linked to the relevant article, that license may permit other uses). Permission may be obtained from ACS for other uses through requests via the RightsLink permission system: http://pubs.acs.org/page/copyright/permissions.html.

Author Information

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  • Corresponding Authors
    • Harry van Goor - Department of Medical Microbiology and Infection Prevention, University of Groningen, University Medical Center Groningen, 9700RB Groningen, The Netherlands;  Email: [email protected]
    • Matthew R. Groves - XB20 Drug Design, Groningen Research Institute of Pharmacy, University of Groningen, 9700 AD Groningen, The Netherlands;  Orcidhttps://orcid.org/0000-0001-9859-5177;  Email: [email protected]
  • Authors
    • Afsaneh Sadremomtaz - XB20 Drug Design, Groningen Research Institute of Pharmacy, University of Groningen, 9700 AD Groningen, The Netherlands
    • Zayana M. Al-Dahmani - XB20 Drug Design, Groningen Research Institute of Pharmacy, University of Groningen, 9700 AD Groningen, The Netherlands;  Department of Medical Microbiology and Infection Prevention, University of Groningen, University Medical Center Groningen, 9700RB Groningen, The Netherlands
    • Angel J. Ruiz-Moreno - XB20 Drug Design, Groningen Research Institute of Pharmacy, University of Groningen, 9700 AD Groningen, The Netherlands;  Departamento de Farmacología, Facultad de Medicina, Universidad Nacional Autónoma de Mexico (UNAM), Ciudad de Mexico 04510, Mexico;  Unidad Periférica de Investigación en Biomedicina Translacional, Facultad de Medicina, Universidad Nacional Autónoma de México (UNAM), Félix Cuevas 540, Ciudad de Mexico 03229, Mexico;  Doctorado en Ciencias Biomédicas, Universidad Nacional Autónoma de México (UNAM), Ciudad de Mexico 04510, Mexico
    • Alessandra Monti - Institute of Biostructures and Bioimaging (IBB)-CNR, Via Mezzocannone, 16, 80134 Napoli, Italy
    • Chao Wang - XB20 Drug Design, Groningen Research Institute of Pharmacy, University of Groningen, 9700 AD Groningen, The Netherlands
    • Taha Azad - Center for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, K1H 8L6 ON, Canada;  Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, K1H 8M5 ON, Canada
    • John C. Bell - Center for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, K1H 8L6 ON, Canada;  Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, K1H 8M5 ON, Canada
    • Nunzianna Doti - Institute of Biostructures and Bioimaging (IBB)-CNR, Via Mezzocannone, 16, 80134 Napoli, Italy
    • Marco A. Velasco-Velázquez - Departamento de Farmacología, Facultad de Medicina, Universidad Nacional Autónoma de Mexico (UNAM), Ciudad de Mexico 04510, Mexico;  Unidad Periférica de Investigación en Biomedicina Translacional, Facultad de Medicina, Universidad Nacional Autónoma de México (UNAM), Félix Cuevas 540, Ciudad de Mexico 03229, Mexico;  Doctorado en Ciencias Biomédicas, Universidad Nacional Autónoma de México (UNAM), Ciudad de Mexico 04510, Mexico;  Orcidhttps://orcid.org/0000-0001-9717-0265
    • Debora de Jong - Department of Medical Microbiology and Infection Prevention, University of Groningen, University Medical Center Groningen, 9700RB Groningen, The Netherlands
    • Jørgen de Jonge - Centre for Infectious Disease Control, National Institute for Public Health and the Environment (RIVM), 3720BA Bilthoven, The Netherlands
    • Jolanda Smit - Department of Medical Microbiology and Infection Prevention, University of Groningen, University Medical Center Groningen, 9700RB Groningen, The Netherlands;  Orcidhttps://orcid.org/0000-0001-6951-1448
    • Alexander Dömling - XB20 Drug Design, Groningen Research Institute of Pharmacy, University of Groningen, 9700 AD Groningen, The Netherlands;  Orcidhttps://orcid.org/0000-0002-9923-8873
  • Author Contributions

    A.S. conceived and designed a library of ACE2 peptides. A.S. implemented computational design pipelines and performed docking protocols and conducted data analyses. A.S. and Z.A. carried out MST experiments. A.J.R.-M., M.A.V.-V., and A.D. implemented MD computational studies and conducted data analyses. A.M. and N.D. provided the ACE2 peptide library and their biophysical characterization. C.W. supported the luciferase assay analysis. T.A. and J.B. engineered ACE2 and S-RBD luciferase construct. D.D.J. and J.D.J. carried out cell assay and performed viral transduction. A.S. wrote the paper, with input from all coauthors. A.S.S.D., M.G., and H.V.G. supervised the work. All coauthors reviewed the paper and provided critical insight and ideas.

  • Notes
    The authors declare the following competing financial interest(s): A.S., M.G., H.V.G., A.M., and N.D. have filed a US patent application entitled on the "Synthetic peptides that block SARS-CoV-2" described in this paper.

Acknowledgments

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This research was supported by private funding by the University of Groningen and University Medical Center Groningen. Support from the project PRIN2017 Prot. 2017M8R7N9 is gratefully acknowledged. Computational studies have implemented by a grant from Universidad Nacional Autónoma de México (UNAM) supercomputer “Miztli” (LANCAD-UNAM-DGTIC-386 2020-2021) and Ph.D. scholarship of A.J.R-M. as a doctoral student from Programa de Doctorado en Ciencias Biomédicas, UNAM with fellowship 584534 from CONACYT.

Abbreviations

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ACE2

angiotensin-converting Enzyme 2

ANOVA

Analysis of variance

CD

circular dichroism

CH3CN

acetonitrile

CTZ

coelenterazine

DMF

dimethylformamide

DIC

N,N′-diisopropylcarbodiimide

DIPEA

diisopropylethylamine

ESI-TOF-MS

electrospray ionization time-of-flight mass spectrometry

FMZ

furimazine

ITC

isothermal titration Calorimetry

IC50

half-maximal inhibitory concentration

LC/MS

liquid chromatography–mass spectrometry

mRNA

messenger RNA

MD

molecular dynamics

PPI

protein–protein interaction

PBS

phosphate-buffered saline

PEG

polyethylene glycol

PBC

periodic boundary conditions

PDA

photodiode array detector

RNA

ribonucleic acid

RMSD

root-mean-square deviation

RMSF

root-mean-square fluctuation

RLU

relative luminescence unit

SARS-CoV-2

severe acute respiratory syndrome coronavirus 2

S-RBD

spike-receptor binding domain

SPR

surface plasmon resonance

SD

standard deviation

TIS

tri-isopropylsilane

TFA

trifluoroacetic acid

TOF

time-of-flight

VEGF

vascular endothelial growth factor

VEGFR

vascular endothelial growth factor receptor

WHO

World Health Organization

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    Computational strategies to combat COVID-19: useful tools to accelerate SARS-CoV-2 and coronavirus research
    Hufsky, Franziska; Lamkiewicz, Kevin; Almeida, Alexandre; Aouacheria, Abdel; Arighi, Cecilia; Bateman, Alex; Baumbach, Jan; Beerenwinkel, Niko; Brandt, Christian; Cacciabue, Marco; Chuguransky, Sara; Drechsel, Oliver; Finn, Robert D.; Fritz, Adrian; Fuchs, Stephan; Hattab, Georges; Hauschild, Anne-Christin; Heider, Dominik; Hoffmann, Marie; Holzer, Martin; Hoops, Stefan; Kaderali, Lars; Kalvari, Ioanna; von Kleist, Max; Kmiecinski, Reno; Kuhnert, Denise; Lasso, Gorka; Libin, Pieter; List, Markus; Lochel, Hannah F.; Martin, Maria J.; Martin, Roman; Matschinske, Julian; McHardy, Alice C.; Mendes, Pedro; Mistry, Jaina; Navratil, Vincent; Nawrocki, Eric P.; O'Toole, Aine Niamh; Ontiveros-Palacios, Nancy; Petrov, Anton I.; Rangel-Pineros, Guillermo; Redaschi, Nicole; Reimering, Susanne; Reinert, Knut; Reyes, Alejandro; Richardson, Lorna; Robertson, David L.; Sadegh, Sepideh; Singer, Joshua B.; Theys, Kristof; Upton, Chris; Welzel, Marius; Williams, Lowri; Marz, Manja
    Briefings in Bioinformatics (2021), 22 (2), 642-663CODEN: BBIMFX; ISSN:1477-4054. (Oxford University Press)
    A review. SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) is a novel virus of the family Coronaviridae. The virus causes the infectious disease COVID-19. The biol. of coronaviruses has been studied for many years. However, bioinformatics tools designed explicitly for SARS-CoV-2 have only recently been developed as a rapid reaction to the need for fast detection, understanding and treatment of COVID-19. To control the ongoing COVID-19 pandemic, it is of utmost importance to get insight into the evolution and pathogenesis of the virus. In this review, we cover bioinformatics workflows and tools for the routine detection of SARS-CoV-2 infection, the reliable anal. of sequencing data, the tracking of the COVID-19 pandemic and evaluation of containment measures, the study of coronavirus evolution, the discovery of potential drug targets and development of therapeutic strategies. For each tool, we briefly describe its use case and how it advances research specifically for SARS-CoV-2. All tools are free to use and available online, either through web applications or public code repositories.
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  4. 4
    V’kovski, P.; Kratzel, A.; Steiner, S.; Stalder, H.; Thiel, V. Coronavirus biology and replication: implications for SARS-CoV-2. Nat. Rev. Microbiol. 2021, 19, 155– 170,  DOI: 10.1038/s41579-020-00468-6
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    Coronavirus biology and replication: implications for SARS-CoV-2
    V'kovski, Philip; Kratzel, Annika; Steiner, Silvio; Stalder, Hanspeter; Thiel, Volker
    Nature Reviews Microbiology (2021), 19 (3), 155-170CODEN: NRMACK; ISSN:1740-1526. (Nature Research)
    A review. Abstr.: The SARS-CoV-2 pandemic and its unprecedented global societal and economic disruptive impact has marked the third zoonotic introduction of a highly pathogenic coronavirus into the human population. Although the previous coronavirus SARS-CoV and MERS-CoV epidemics raised awareness of the need for clin. available therapeutic or preventive interventions, to date, no treatments with proven efficacy are available. The development of effective intervention strategies relies on the knowledge of mol. and cellular mechanisms of coronavirus infections, which highlights the significance of studying virus-host interactions at the mol. level to identify targets for antiviral intervention and to elucidate crit. viral and host determinants that are decisive for the development of severe disease. In this Review, we summarize the first discoveries that shape our current understanding of SARS-CoV-2 infection throughout the intracellular viral life cycle and relate that to our knowledge of coronavirus biol. The elucidation of similarities and differences between SARS-CoV-2 and other coronaviruses will support future preparedness and strategies to combat coronavirus infections.
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  5. 5
    Zhang, L.; Lin, D.; Sun, X.; Curth, U.; Drosten, C.; Sauerhering, L.; Becker, S.; Rox, K.; Hilgenfeld, R. Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved α-ketoamide inhibitors. Science 2020, 368, 409– 412,  DOI: 10.1126/science.abb3405
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    Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved α-ketoamide inhibitors
    Zhang, Linlin; Lin, Daizong; Sun, Xinyuanyuan; Curth, Ute; Drosten, Christian; Sauerhering, Lucie; Becker, Stephan; Rox, Katharina; Hilgenfeld, Rolf
    Science (Washington, DC, United States) (2020), 368 (6489), 409-412CODEN: SCIEAS; ISSN:1095-9203. (American Association for the Advancement of Science)
    The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) is a global health emergency. An attractive drug target among coronaviruses is the main protease (Mpro, also called 3CLpro) because of its essential role in processing the polyproteins that are translated from the viral RNA. We report the x-ray structures of the unliganded SARS-CoV-2 Mpro and its complex with an α-ketoamide inhibitor. This was derived from a previously designed inhibitor but with the P3-P2 amide bond incorporated into a pyridone ring to enhance the half-life of the compd. in plasma. On the basis of the unliganded structure, we developed the lead compd. into a potent inhibitor of the SARS-CoV-2 Mpro. The pharmacokinetic characterization of the optimized inhibitor reveals a pronounced lung tropism and suitability for administration by the inhalative route.
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  6. 6
    Jin, Z.; Du, X.; Xu, Y.; Deng, Y.; Liu, M.; Zhao, Y.; Zhang, B.; Li, X.; Zhang, L.; Peng, C.; Duan, Y.; Yu, J.; Wang, L.; Yang, K.; Liu, F.; Jiang, R.; Yang, X.; You, T.; Liu, X.; Yang, X.; Bai, F.; Liu, H.; Liu, X.; Guddat, L. W.; Xu, W.; Xiao, G.; Qin, C.; Shi, Z.; Jiang, H.; Rao, Z.; Yang, H. Structure of Mpro from SARS-CoV-2 and discovery of its inhibitors. Nature 2020, 582, 289– 293,  DOI: 10.1038/s41586-020-2223-y
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    6
    Structure of Mpro from SARS-CoV-2 and discovery of its inhibitors
    Jin, Zhenming; Du, Xiaoyu; Xu, Yechun; Deng, Yongqiang; Liu, Meiqin; Zhao, Yao; Zhang, Bing; Li, Xiaofeng; Zhang, Leike; Peng, Chao; Duan, Yinkai; Yu, Jing; Wang, Lin; Yang, Kailin; Liu, Fengjiang; Jiang, Rendi; Yang, Xinglou; You, Tian; Liu, Xiaoce; Yang, Xiuna; Bai, Fang; Liu, Hong; Liu, Xiang; Guddat, Luke W.; Xu, Wenqing; Xiao, Gengfu; Qin, Chengfeng; Shi, Zhengli; Jiang, Hualiang; Rao, Zihe; Yang, Haitao
    Nature (London, United Kingdom) (2020), 582 (7811), 289-293CODEN: NATUAS; ISSN:0028-0836. (Nature Research)
    Abstr.: A new coronavirus, known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is the etiol. agent responsible for the 2019-2020 viral pneumonia outbreak of coronavirus disease 2019 (COVID-19). Currently, there are no targeted therapeutic agents for the treatment of this disease, and effective treatment options remain very limited. Here, we describe the results of a program that aimed to rapidly discover lead compds. for clin. use, by combining structure-assisted drug design, virtual drug screening and high-throughput screening. This program focused on identifying drug leads that target main protease (Mpro) of SARS-CoV-2: Mpro is a key enzyme of coronaviruses and has a pivotal role in mediating viral replication and transcription, making it an attractive drug target for SARS-CoV-2. We identified a mechanism-based inhibitor (N3) by computer-aided drug design, and then detd. the crystal structure of Mpro of SARS-CoV-2 in complex with this compd. Through a combination of structure-based virtual and high-throughput screening, we assayed more than 10,000 compds.-including approved drugs, drug candidates in clin. trials and other pharmacol. active compds.-as inhibitors of Mpro. Six of these compds. inhibited Mpro, showing half-maximal inhibitory concn. values that ranged from 0.67 to 21.4μM. One of these compds. (ebselen) also exhibited promising antiviral activity in cell-based assays. Our results demonstrate the efficacy of our screening strategy, which can lead to the rapid discovery of drug leads with clin. potential in response to new infectious diseases for which no specific drugs or vaccines are available.
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    Hussain, S.; Xie, Y. J.; Li, D.; Malik, S. I.; Hou, J. C.; Leung, E. L.; Fan, X. X. Current strategies against COVID-19. Chin. Med. 2020, 15, 70,  DOI: 10.1186/s13020-020-00353-7
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    Current strategies against COVID-19
    Hussain, Shahid; Xie, Ya-Jia; Li, Dan; Malik, Shaukat Iqbal; Hou, Jin-cai; Leung, Elaine Lai-Han; Fan, Xing-Xing
    Chinese Medicine (London, United Kingdom) (2020), 15 (1), 70CODEN: CMHEBK; ISSN:1749-8546. (BioMed Central Ltd.)
    A review. Abstr.: Coronavirus disease (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) recently was declared a pandemic by world health organization (WHO) Due to sudden outbreaks, currently, no completely effective vaccine or drug is clin. approved. Several therapeutic strategies can be envisaged to prevent further mortality and morbidity. Based on the past contribution of traditional Chinese medicines (TCM) and immune-based therapies as a treatment option in crucial pathogen outbreaks, we aimed to summarize potential therapeutic strategies that could be helpful to stop further spread of SARS-CoV-2 by effecting its structural components or modulation of immune responses. A review. Several TCM with or without modification could be effective against the structural protein, enzymes, and nucleic acid should be tested from available libraries or to identify their immune-stimulatory activities to enhance several antiviral biol. agents for effective elimination of SARS-CoV-2 from the host. TCM is not only effective in the direct inhibition of virus attachment and internalization in a cell but can also prevent their replication and can also help to boost up host immune response. Immune-modulatory effects of TCMs may lead to new medications and can guide us for the scientific validity of drug development. Besides, we also summarized the effective therapies in clin. for controlling inflammation. This review will be not only helpful for the current situation of COVID-19, but can also play a major role in such epidemics in the future.
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  8. 8
    Choudhary, S.; Malik, Y. S.; Tomar, S. Identification of SARS-CoV-2 cell entry inhibitors by drug repurposing using in silico structure-based virtual screening approach. Front. Immunol. 2020, 11, 1664,  DOI: 10.3389/fimmu.2020.01664
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    8
    Identification of SARS-CoV-2 cell entry inhibitors by drug repurposing using in silico structure-based virtual screening approach
    Choudhary, Shweta; Malik, Yashpal S.; Tomar, Shailly
    Frontiers in Immunology (2020), 11 (), 1664CODEN: FIRMCW; ISSN:1664-3224. (Frontiers Media S.A.)
    The rapidly spreading, highly contagious and pathogenic SARS-coronavirus 2 (SARS-CoV-2) assocd. Coronavirus Disease 2019 (COVID-19) has been declared as a pandemic by the World Health Organization (WHO). The novel 2019 SARS-CoV-2 enters the host cell by binding of the viral surface spike glycoprotein (S-protein) to cellular angiotensin converting enzyme 2 (ACE2) receptor. The virus specific mol. interaction with the host cell represents a promising therapeutic target for identifying SARS-CoV-2 antiviral drugs. The repurposing of drugs can provide a rapid and potential cure toward exponentially expanding COVID-19. Thereto, high throughput virtual screening approach was used to investigate FDA approved LOPAC library drugs against both the receptor binding domain of spike protein (S-RBD) and ACE2 host cell receptor. Primary screening identified a few promising mols. for both the targets, which were further analyzed in details by their binding energy, binding modes through mol. docking, dynamics and simulations. Evidently, GR 127935 hydrochloride hydrate, GNF-5, RS504393, TNP, and eptifibatide acetate were found binding to virus binding motifs of ACE2 receptor. Addnl., KT203, BMS195614, KT185, RS504393, and GSK1838705A were identified to bind at the receptor binding site on the viral S-protein. These identified mols. may effectively assist in controlling the rapid spread of SARS-CoV-2 by not only potentially inhibiting the virus at entry step but are also hypothesized to act as anti-inflammatory agents, which could impart relief in lung inflammation. Timely identification and detn. of an effective drug to combat and tranquilize the COVID-19 global crisis is the utmost need of hour. Further, prompt in vivo testing to validate the anti-SARS-CoV-2 inhibition efficiency by these mols. could save lives is justified.
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    Shyr, Z. A.; Gorshkov, K.; Chen, C. Z.; Zheng, W. Drug discovery strategies for SARS-CoV-2. J. Pharmacol. Exp. Ther. 2020, 375, 127– 138,  DOI: 10.1124/jpet.120.000123
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    Drug discovery strategies for SARS-CoV-2
    Shyr, Zeenat A.; Gorshkov, Kirill; Chen, Catherine Z.; Zheng, Wei
    Journal of Pharmacology and Experimental Therapeutics (2020), 375 (1), 127-138CODEN: JPETAB; ISSN:1521-0103. (American Society for Pharmacology and Experimental Therapeutics)
    A review. Coronavirus disease 2019 (COVID-19) is a novel disease caused by the severe acute respiratory syndrome coronavirus (SARS-CoV)-2 virus that was first detected in Dec. of 2019 in Wuhan, China, and has rapidly spread worldwide. The search for a suitable vaccine as well as effective therapeutics for the treatment of COVID-19 is underway. Drug repurposing screens provide a useful and effective soln. for identifying potential therapeutics against SARS-CoV-2. For example, the exptl. drug remdesivir, originally developed for Ebola virus infections, has been approved by the US Food and Drug Administration as an emergency use treatment of COVID-19. However, the efficacy and toxicity of this drug need further improvements. In this review, we discuss recent findings on the pathol. of coronaviruses and the drug targets for the treatment of COVID-19. Both SARS-CoV-2-specific inhibitors and broad-spectrum anticoronavirus drugs against SARS-CoV, Middle East respiratory syndrome coronavirus, and SARS-CoV-2 will be valuable addns. to the anti-SARS-CoV-2 armament. A multitarget treatment approach with synergistic drug combinations contg. different mechanisms of action may be a practical therapeutic strategy for the treatment of severe COVID-19.
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  10. 10
    Gil, C.; Ginex, T.; Maestro, I.; Nozal, V.; Barrado-Gil, L.; Cuesta-Geijo, M.Á.; Urquiza, J.; Ramírez, D.; Alonso, C.; Campillo, N. E.; Martinez, A. COVID-19: drug targets and potential treatments. J. Med. Chem. 2020, 63, 12359– 12386,  DOI: 10.1021/acs.jmedchem.0c00606
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    COVID-19: Drug Targets and Potential Treatments
    Gil, Carmen; Ginex, Tiziana; Maestro, Ines; Nozal, Vanesa; Barrado-Gil, Lucia; Cuesta-Geijo, Miguel Angel; Urquiza, Jesus; Ramirez, David; Alonso, Covadonga; Campillo, Nuria E.; Martinez, Ana
    Journal of Medicinal Chemistry (2020), 63 (21), 12359-12386CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
    A review. Currently, the authors are immersed in a pandemic caused by the emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which severely threatens public health worldwide. Until now, no drug or vaccine has been approved to treat the severe disease caused by this coronavirus, COVID-19. The authors will focus on the main virus-based and host-based targets that can guide medicinal chem. efforts to discover new drugs for this devastating disease. In principle, all CoVs enzymes and proteins involved in viral replication and the control of host cellular machineries are potentially druggable targets in the search for therapeutic options for SARS-CoV-2. This perspective provides an overview of the main targets from a structural point of view, together with reported therapeutic compds. with activity against SARS-CoV-2 and/or other CoVs. Also, the role of innate immune response to coronavirus infection and the related therapeutic options will be presented.
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    Catanzaro, M.; Fagiani, F.; Racchi, M.; Corsini, E.; Govoni, S.; Lanni, C. Immune response in COVID-19: addressing a pharmacological challenge by targeting pathways triggered by SARS-CoV-2. Signal Transduct Target Ther. 2020, 5, 84,  DOI: 10.1038/s41392-020-0191-1
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    Immune response in COVID-19: addressing a pharmacological challenge by targeting pathways triggered by SARS-CoV-2
    Catanzaro Michele; Fagiani Francesca; Racchi Marco; Govoni Stefano; Lanni Cristina; Fagiani Francesca; Corsini Emanuela
    Signal transduction and targeted therapy (2020), 5 (1), 84 ISSN:.
    To date, no vaccines or effective drugs have been approved to prevent or treat COVID-19 and the current standard care relies on supportive treatments. Therefore, based on the fast and global spread of the virus, urgent investigations are warranted in order to develop preventive and therapeutic drugs. In this regard, treatments addressing the immunopathology of SARS-CoV-2 infection have become a major focus. Notably, while a rapid and well-coordinated immune response represents the first line of defense against viral infection, excessive inflammatory innate response and impaired adaptive host immune defense may lead to tissue damage both at the site of virus entry and at systemic level. Several studies highlight relevant changes occurring both in innate and adaptive immune system in COVID-19 patients. In particular, the massive cytokine and chemokine release, the so-called "cytokine storm", clearly reflects a widespread uncontrolled dysregulation of the host immune defense. Although the prospective of counteracting cytokine storm is compelling, a major limitation relies on the limited understanding of the immune signaling pathways triggered by SARS-CoV-2 infection. The identification of signaling pathways altered during viral infections may help to unravel the most relevant molecular cascades implicated in biological processes mediating viral infections and to unveil key molecular players that may be targeted. Thus, given the key role of the immune system in COVID-19, a deeper understanding of the mechanism behind the immune dysregulation might give us clues for the clinical management of the severe cases and for preventing the transition from mild to severe stages.
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    Wu, C.; Liu, Y.; Yang, Y.; Zhang, P.; Zhong, W.; Wang, Y.; Wang, Q.; Xu, Y.; Li, M.; Li, X.; Zheng, M.; Chen, L.; Li, H. Analysis of therapeutic targets for SARS-CoV-2 and discovery of potential drugs by computational methods. Acta Pharm. Sin. B 2020, 10, 766– 788,  DOI: 10.1016/j.apsb.2020.02.008
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    Analysis of therapeutic targets for SARS-CoV-2 and discovery of potential drugs by computational methods
    Wu, Canrong; Liu, Yang; Yang, Yueying; Zhang, Peng; Zhong, Wu; Wang, Yali; Wang, Qiqi; Xu, Yang; Li, Mingxue; Li, Xingzhou; Zheng, Mengzhu; Chen, Lixia; Li, Hua
    Acta Pharmaceutica Sinica B (2020), 10 (5), 766-788CODEN: APSBCW; ISSN:2211-3835. (Elsevier B.V.)
    SARS-CoV-2 has caused tens of thousands of infections and more than one thousand deaths. There are currently no registered therapies for treating coronavirus infections. Because of time consuming process of new drug development, drug repositioning may be the only soln. to the epidemic of sudden infectious diseases. We systematically analyzed all the proteins encoded by SARS-CoV-2 genes, compared them with proteins from other coronaviruses, predicted their structures, and built 19 structures that could be done by homol. modeling. By performing target-based virtual ligand screening, a total of 21 targets (including two human targets) were screened against compd. libraries including ZINC drug database and our own database of natural products. Structure and screening results of important targets such as 3-chymotrypsin-like protease (3CLpro), Spike, RNA-dependent RNA polymerase (RdRp), and papain like protease (PLpro) were discussed in detail. In addn., a database of 78 commonly used anti-viral drugs including those currently on the market and undergoing clin. trials for SARS-CoV-2 was constructed. Possible targets of these compds. and potential drugs acting on a certain target were predicted. This study will provide new lead compds. and targets for further in vitro and in vivo studies of SARS-CoV-2, new insights for those drugs currently ongoing clin. studies, and also possible new strategies for drug repositioning to treat SARS-CoV-2 infections.
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    VanPatten, S.; He, M.; Altiti, A.; F Cheng, K.; Ghanem, M. H.; Al-Abed, Y. Evidence supporting the use of peptides and peptidomimetics as potential SARS-CoV-2 (COVID-19) therapeutics. Future Med. Chem. 2020, 12, 1647– 1656,  DOI: 10.4155/fmc-2020-0180
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    Evidence supporting the use of peptides and peptidomimetics as potential SARS-CoV-2 (COVID-19) therapeutics
    VanPatten, Sonya; He, Mingzhu; Altiti, Ahmad; F Cheng, Kai; Ghanem, Mustafa H.; Al-Abed, Yousef
    Future Medicinal Chemistry (2020), 12 (18), 1647-1656CODEN: FMCUA7; ISSN:1756-8919. (Newlands Press Ltd.)
    A review. During a disease outbreak/pandemic situation such as COVID-19, researchers are in a prime position to identify and develop peptide-based therapies, which could be more rapidly and cost-effectively advanced into a clin. setting. One drawback of natural peptide drugs, however, is their proteolytic instability; peptidomimetics can help to overcome this caveat. In this review, we summarize peptide and peptide-based therapeutics that target one main entry pathway of SARS-CoV-2, which involves the host ACE2 receptor and viral spike (S) protein interaction. Furthermore, we discuss the advantages of peptidomimetics and other potential targets that have been studied using peptide-based therapeutics for COVID-19.
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    Smith, M. C.; Gestwicki, J. E. Features of protein-protein interactions that translate into potent inhibitors: topology, surface area and affinity. Expert Rev. Mol. Med. 2012, 14, 14– 16,  DOI: 10.1017/erm.2012.10
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    Josephson, K.; Ricardo, A.; Szostak, J. W. mRNA display: from basic principles to macrocycle drug discovery. Drug Discovery Today 2014, 19, 388– 99,  DOI: 10.1016/j.drudis.2013.10.011
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    mRNA display: from basic principles to macrocycle drug discovery
    Josephson, Kristopher; Ricardo, Alonso; Szostak, Jack W.
    Drug Discovery Today (2014), 19 (4), 388-399CODEN: DDTOFS; ISSN:1359-6446. (Elsevier Ltd.)
    A review. We describe a new discovery technol. that uses mRNA-display to rapidly synthesize and screen macrocyclic peptide libraries to explore a valuable region of chem. space typified by natural products. This technol. allows high-affinity peptidic macrocycles contg. modified backbones and unnatural side chains to be readily selected based on target binding. Success stories covering the first examples of these libraries suggest that they could be used for the discovery of intracellular protein-protein interaction inhibitors, highly selective enzyme inhibitors or synthetic replacements for monoclonal antibodies. The review concludes with a look to the future regarding how this technol. might be improved with respect to library design for cell permeability and bioavailability.
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    Voysey, M.; Clemens; Madhi, S.; Weckx, L. Y.; Folegatti, P. M. Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK. Lancet 2021, 397, 99– 111,  DOI: 10.1016/S0140-6736(20)32661-1
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    Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomized controlled trials in Brazil, South Africa, and the UK
    Voysey, Merryn; Clemens, Sue Ann Costa; Madhi, Shabir A.; Weckx, Lily Y.; Folegatti, Pedro M.; Aley, Parvinder K.; Angus, Brian; Baillie, Vicky L.; Barnabas, Shaun L.; Bhorat, Qasim E.; Bibi, Sagida; Briner, Carmen; Cicconi, Paola; Collins, Andrea M.; Colin-Jones, Rachel; Cutland, Clare L.; Darton, Thomas C.; Dheda, Keertan; Duncan, Christopher J. A.; Emary, Katherine R. W.; Ewer, Katie J.; Fairlie, Lee; Faust, Saul N.; Feng, Shuo; Ferreira, Daniela M.; Finn, Adam; Goodman, Anna L.; Green, Catherine M.; Green, Christopher A.; Heath, Paul T.; Hill, Catherine; Hill, Helen; Hirsch, Ian; Hodgson, Susanne H. C.; Izu, Alane; Jackson, Susan; Jenkin, Daniel; Joe, Carina C. D.; Kerridge, Simon; Koen, Anthonet; Kwatra, Gaurav; Lazarus, Rajeka; Lawrie, Alison M.; Lelliott, Alice; Libri, Vincenzo; Lillie, Patrick J.; Mallory, Raburn; Mendes, Ana V. A.; Milan, Eveline P.; Minassian, Angela M.; McGregor, Alastair; Morrison, Hazel; Mujadidi, Yama F.; Nana, Anusha; O'Reilly, Peter J.; Padayachee, Sherman D.; Pittella, Ana; Plested, Emma; Pollock, Katrina M.; Ramasamy, Maheshi N.; Rhead, Sarah; Schwarzbold, Alexandre V.; Singh, Nisha; Smith, Andrew; Song, Rinn; Snape, Matthew D.; Sprinz, Eduardo; Sutherland, Rebecca K.; Tarrant, Richard; Thomson, Emma C.; Torok, M. Estee; Toshner, Mark; Turner, David P. J.; Vekemans, Johan; Villafana, Tonya L.; Watson, Marion E. E.; Williams, Christopher J.; Douglas, Alexander D.; Hill, Adrian V. S.; Lambe, Teresa; Gilbert, Sarah C.; Pollard, Andrew J.
    Lancet (2021), 397 (10269), 99-111CODEN: LANCAO; ISSN:0140-6736. (Elsevier Ltd.)
    A safe and efficacious vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), if deployed with high coverage, could contribute to the control of the COVID-19 pandemic. We evaluated the safety and efficacy of the ChAdOx1 nCoV-19 vaccine in a pooled interim anal. of four trials. This anal. includes data from four ongoing blinded, randomized, controlled trials done across the UK, Brazil, and South Africa. Participants aged 18 years and older were randomly assigned (1:1) to ChAdOx1 nCoV-19 vaccine or control (meningococcal group A, C, W, and Y conjugate vaccine or saline). Participants in the ChAdOx1 nCoV-19 group received two doses contg. 5 x 1010 viral particles (std. dose; SD/SD cohort); a subset in the UK trial received a half dose as their first dose (low dose) and a std. dose as their second dose (LD/SD cohort). The primary efficacy anal. included symptomatic COVID-19 in seroneg. participants with a nucleic acid amplification test-pos. swab more than 14 days after a second dose of vaccine. Participants were analyzed according to treatment received, with data cutoff on Nov 4, 2020. Vaccine efficacy was calcd. as 1 - relative risk derived from a robust Poisson regression model adjusted for age. Studies are registered at ISRCTN89951424 and ClinicalTrials.gov, NCT04324606, NCT04400838, and NCT04444674. Between Apr. 23 and Nov 4, 2020, 23,848 participants were enrolled and 11,636 participants (7548 in the UK, 4088 in Brazil) were included in the interim primary efficacy anal. In participants who received two std. doses, vaccine efficacy was 62.1% (95% CI 41.0-75.7; 27 [0.6%] of 4440 in the ChAdOx1 nCoV-19 group vs. 71 [1.6%] of 4455 in the control group) and in participants who received a low dose followed by a std. dose, efficacy was 90.0% (67.4-97.0; three [0.2%] of 1367 vs 30 [2.2%] of 1374; pinteraction=0.010). Overall vaccine efficacy across both groups was 70.4% (95.8% CI 54.8-80.6; 30 [0.5%] of 5807 vs 101 [1.7%] of 5829). From 21 days after the first dose, there were ten cases hospitalized for COVID-19, all in the control arm; two were classified as severe COVID-19, including one death. There were 74,341 person-months of safety follow-up (median 3.4 mo, IQR 1.3-4.8): 175 severe adverse events occurred in 168 participants, 84 events in the ChAdOx1 nCoV-19 group and 91 in the control group. Three events were classified as possibly related to a vaccine: one in the ChAdOx1 nCoV-19 group, one in the control group, and one in a participant who remains masked to group allocation. ChAdOx1 nCoV-19 has an acceptable safety profile and has been found to be efficacious against symptomatic COVID-19 in this interim anal. of ongoing clin. trials.
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    Polack, F. P.; Thomas, S. J.; Kitchin, N. Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine. N. Engl. J. Med. 2020, 383, 2603– 2615,  DOI: 10.1056/NEJMoa2034577
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    Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine
    Polack, Fernando P.; Thomas, Stephen J.; Kitchin, Nicholas; Absalon, Judith; Gurtman, Alejandra; Lockhart, Stephen; Perez, John L.; Marc, Gonzalo Perez; Moreira, Edson D.; Zerbini, Cristiano; Bailey, Ruth; Swanson, Kena A.; Roychoudhury, Satrajit; Koury, Kenneth; Li, Ping; Kalina, Warren V.; Cooper, David; Frenck, Robert W., Jr.; Hammitt, Laura L.; Tureci, Ozlem; Nell, Haylene; Schaefer, Axel; Unal, Serhat; Tresnan, Dina B.; Mather, Susan; Dormitzer, Philip R.; Sahin, Ugur; Jansen, Kathrin U.; Gruber, William C.
    New England Journal of Medicine (2020), 383 (27), 2603-2615CODEN: NEJMAG; ISSN:1533-4406. (Massachusetts Medical Society)
    A review. Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the resulting coronavirus disease 2019 (Covid-19) have afflicted tens of millions of people in a worldwide pandemic. Safe and effective vaccines are needed urgently. methods In an ongoing multinational, placebo-controlled, observer-blinded, pivotal efficacy trial, we randomly assigned persons 16 years of age or older in a 1:1 ratio to receive two doses, 21 days apart, of either placebo or the BNT162b2 vaccine candidate (30μg per dose). BNT162b2 is a lipid nanoparticle-formulated, nucleoside-modified RNA vaccine that encodes a prefusion stabilized, membrane-anchored SARS-CoV-2 full-length spike protein. The primary end points were efficacy of the vaccine against lab.-confirmed Covid-19 and safety. results A total of 43,548 participants underwent randomization, of whom 43,448 received injections: 21,720 with BNT162b2 and 21,728 with placebo. There were 8 cases of Covid-19 with onset at least 7 days after the second dose among participants assigned to receive BNT162b2 and 162 cases among those assigned to placebo; BNT162b2 was 95% effective in preventing Covid-19 (95% credible interval, 90.3 to 97.6). Similar vaccine efficacy (generally 90 to 100%) was obsd. across subgroups defined by age, sex, race, ethnicity, baseline body-mass index, and the presence of coexisting conditions. Among 10 cases of severe Covid-19 with onset after the first dose, 9 occurred in placebo recipients and 1 in a BNT162b2 recipient. The safety profile of BNT162b2 was characterized by short-term, mild-to-moderate pain at the injection site, fatigue, and headache. The incidence of serious adverse events was low and was similar in the vaccine and placebo groups. conclusions A two-dose regimen of BNT162b2 conferred 95% protection against Covid-19 in persons 16 years of age or older. Safety over a median of 2 mo was similar to that of other viral vaccines.
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    Baden, L. R.; El Sahly, H. M.; Essink, B. Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine. N. Engl. J. Med. 2021, 384, 403– 416,  DOI: 10.1056/NEJMoa2035389
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    Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine
    Baden, L. R.; El Sahly, H. M.; Essink, B.; Kotloff, K.; Frey, S.; Novak, R.; Diemert, D.; Spector, S. A.; Rouphael, N.; Creech, C. B.; McGettigan, J.; Khetan, S.; Segall, N.; Solis, J.; Brosz, A.; Fierro, C.; Schwartz, H.; Neuzil, K.; Corey, L.; Gilbert, P.; Janes, H.; Follmann, D.; Marovich, M.; Mascola, J.; Polakowski, L.; Ledgerwood, J.; Graham, B. S.; Bennett, H.; Pajon, R.; Knightly, C.; Leav, B.; Deng, W.; Zhou, H.; Han, S.; Ivarsson, M.; Miller, J.; Zaks, T.
    New England Journal of Medicine (2021), 384 (5), 403-416CODEN: NEJMAG; ISSN:1533-4406. (Massachusetts Medical Society)
    Vaccines are needed to prevent coronavirus disease 2019 (Covid-19) and to protect persons who are at high risk for complications. The mRNA-1273 vaccine is a lipid nanoparticle-encapsulated mRNA-based vaccine that encodes the prefusion stabilized full-length spike protein of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes Covid-19. This phase 3 randomized, observer-blinded, placebo-controlled trial was conducted at 99 centers across the United States. Persons at high risk for SARS-CoV-2 infection or its complications were randomly assigned in a 1:1 ratio to receive two i.m. injections of mRNA-1273 (100μg) or placebo 28 days apart. The primary end point was prevention of Covid-19 illness with onset at least 14 days after the second injection in participants who had not previously been infected with SARS-CoV-2. The trial enrolled 30,420 volunteers who were randomly assigned in a 1:1 ratio to receive either vaccine or placebo (15,210 participants in each group). More than 96% of participants received both injections, and 2.2% had evidence (serol., virol., or both) of SARS-CoV-2 infection at baseline. Symptomatic Covid-19 illness was confirmed in 185 participants in the placebo group (56.5 per 1000 person-years; 95% confidence interval [CI], 48.7 to 65.3) and in 11 participants in the mRNA-1273 group (3.3 per 1000 person-years; 95% CI, 1.7 to 6.0); vaccine efficacy was 94.1% (95% CI, 89.3 to 96.8%; P<0.001). Efficacy was similar across key secondary analyses, including assessment 14 days after the first dose, analyses that included participants who had evidence of SARS-CoV-2 infection at baseline, and analyses in participants 65 years of age or older. Severe Covid-19 occurred in 30 participants, with one fatality; all 30 were in the placebo group. Moderate, transient reactogenicity after vaccination occurred more frequently in the mRNA-1273 group. Serious adverse events were rare, and the incidence was similar in the two groups. The mRNA-1273 vaccine showed 94.1% efficacy at preventing Covid-19 illness, including severe disease. Aside from transient local and systemic reactions, no safety concerns were identified.
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    Kovyrshina, A. V.; Dolzhikova, I. V.; Grousova, D. M. A heterologous virus-vectored vaccine for prevention of middle east respiratory syndrome induces long protective immune response against MERS-CoV. Immunologiya 2020, 41, 135– 43,  DOI: 10.33029/0206-4952-2020-41-2-135-143
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    Logunov, D. Y.; Dolzhikova, I. V.; Zubkova, O. V. Safety and immunogenicity of an rAd26 and rAd5 vector-based heterologous prime-boost COVID-19 vaccine in two formulations: two open, non-randomised phase 1/2 studies from Russia. Lancet 2020, 396, 887– 97,  DOI: 10.1016/S0140-6736(20)31866-3
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    Safety and immunogenicity of an rAd26 and rAd5 vector-based heterologous prime-boost COVID-19 vaccine in two formulations: two open, non-randomised phase 1/2 studies from Russia
    Logunov, Denis Y.; Dolzhikova, Inna V.; Zubkova, Olga V.; Tukhvatullin, Amir I.; Shcheblyakov, Dmitry V.; Dzharullaeva, Alina S.; Grousova, Daria M.; Erokhova, Alina S.; Kovyrshina, Anna V.; Botikov, Andrei G.; Izhaeva, Fatima M.; Popova, Olga; Ozharovskaya, Tatiana A.; Esmagambetov, Ilias B.; Favorskaya, Irina A.; Zrelkin, Denis I.; Voronina, Daria V.; Shcherbinin, Dmitry N.; Semikhin, Alexander S.; Simakova, Yana V.; Tokarskaya, Elizaveta A.; Lubenets, Nadezhda L.; Egorova, Daria A.; Shmarov, Maksim M.; Nikitenko, Natalia A.; Morozova, Lola F.; Smolyarchuk, Elena A.; Kryukov, Evgeny V.; Babira, Vladimir F.; Borisevich, Sergei V.; Naroditsky, Boris S.; Gintsburg, Alexander L.
    Lancet (2020), 396 (10255), 887-897CODEN: LANCAO; ISSN:0140-6736. (Elsevier Ltd.)
    We developed a heterologous COVID-19 vaccine consisting of 2 components, a recombinant adenovirus type 26 (rAd26) vector and a recombinant adenovirus type 5 (rAd5) vector, both carrying the gene for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike glycoprotein (rAd26-S and rAd5-S). We aimed to assess the safety and immunogenicity of 2 formulations (frozen and lyophilized) of this vaccine. We did 2 open, non-randomized phase 1/2 studies at 2 hospitals in Russia. We enrolled healthy adult volunteers (men and women) aged 18-60 yr to both studies. In phase 1 of each study, we administered i.m. on day 0 either 1 dose of rAd26-S or 1 dose of rAd5-S and assessed the safety of the 2 components for 28 days. In phase 2 of the study, which began no earlier than 5 days after phase 1 vaccination, we administered i.m. a prime-boost vaccination, with rAd26-S given on day 0 and rAd5-S on day 21. Primary outcome measures were antigen-specific humoral immunity (SARS-CoV-2-specific antibodies measured by ELISA on days 0, 14, 21, 28, and 42) and safety (no. of participants with adverse events monitored throughout the study). Secondary outcome measures were antigen-specific cellular immunity (T-cell responses and interferon-γ concn.) and change in neutralizing antibodies (detected with a SARS-CoV-2 neutralization assay). These trials are registered with ClinicalTrials.gov, NCT04436471 and NCT04437875. Between June 18 and Aug 3, 2020, we enrolled 76 participants to the 2 studies (38 in each study). In each study, 9 volunteers received rAd26-S in phase 1, 9 received rAd5-S in phase 1, and 20 received rAd26-S and rAd5-S in phase 2. Both vaccine formulations were safe and well tolerated. The most common adverse events were pain at injection site (44 [58%]), hyperthermia (38 [50%]), headache (32 [42%]), asthenia (21 [28%]), and muscle and joint pain (18 [24%]). Most adverse events were mild and no serious adverse events were detected. All participants produced antibodies to SARS-CoV-2 glycoprotein. At day 42, receptor binding domain-specific IgG titers were 14 703 with the frozen formulation and 11,143 with the lyophilized formulation, and neutralizing antibodies were 49·25 with the frozen formulation and 45·95 with the lyophilized formulation, with a seroconversion rate of 100%. Cell-mediated responses were detected in all participants at day 28, with median cell proliferation of 2.5% CD4+ and 1.3% CD8+ with the frozen formulation, and a median cell proliferation of 1.3% CD4+ and 1.1% CD8+ with the lyophilized formulation. The heterologous rAd26 and rAd5 vector-based COVID-19 vaccine has a good safety profile and induced strong humoral and cellular immune responses in participants. Further investigation is needed of the effectiveness of this vaccine for prevention of COVID-19. Ministry of Health of the Russian Federation.
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    Logunov, D. Y.; Dolzhikova, I. V.; Shcheblyakov, D. V.; Tukhvatulin, A. Safety and efficacy of an rAd26 and rAd5 vector-based heterologous prime-boost COVID-19 vaccine: an interim analysis of a randomised controlled phase 3 trial in Russia. Lancet 2021, 397, 671,  DOI: 10.1016/S0140-6736(21)00234-8
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    22
    Safety and efficacy of an rAd26 and rAd5 vector-based heterologous prime-boost COVID-19 vaccine: an interim analysis of a randomized controlled phase 3 trial in Russia
    Logunov, Denis Y.; Dolzhikova, Inna V.; Shcheblyakov, Dmitry V.; Tukhvatulin, Amir I.; Zubkova, Olga V.; Dzharullaeva, Alina S.; Kovyrshina, Anna V.; Lubenets, Nadezhda L.; Grousova, Daria M.; Erokhova, Alina S.; Botikov, Andrei G.; Izhaeva, Fatima M.; Popova, Olga; Ozharovskaya, Tatiana A.; Esmagambetov, Ilias B.; Favorskaya, Irina A.; Zrelkin, Denis I.; Voronina, Daria V.; Shcherbinin, Dmitry N.; Semikhin, Alexander S.; Simakova, Yana V.; Tokarskaya, Elizaveta A.; Egorova, Daria A.; Shmarov, Maksim M.; Nikitenko, Natalia A.; Gushchin, Vladimir A.; Smolyarchuk, Elena A.; Zyryanov, Sergey K.; Borisevich, Sergei V.; Naroditsky, Boris S.; Gintsburg, Alexander L.
    Lancet (2021), 397 (10275), 671-681CODEN: LANCAO; ISSN:0140-6736. (Elsevier Ltd.)
    A heterologous recombinant adenovirus (rAd)-based vaccine, Gam-COVID-Vac (Sputnik V), showed a good safety profile and induced strong humoral and cellular immune responses in participants in phase 1/2 clin. trials. Here, we report preliminary results on the efficacy and safety of Gam-COVID-Vac from the interim anal. of this phase 3 trial. We did a randomized, double-blind, placebo-controlled, phase 3 trial at 25 hospitals and polyclinics in Moscow, Russia. We included participants aged at least 18 years, with neg. SARS-CoV-2 PCR and IgG and IgM tests, no infectious diseases in the 14 days before enrollment, and no other vaccinations in the 30 days before enrollment. Participants were randomly assigned (3:1) to receive vaccine or placebo, with stratification by age group. Investigators, participants, and all study staff were masked to group assignment. The vaccine was administered (0·5 mL/dose) i.m. in a prime-boost regimen: a 21-day interval between the first dose (rAd26) and the second dose (rAd5), both vectors carrying the gene for the full-length SARS-CoV-2 glycoprotein S. The primary outcome was the proportion of participants with PCR-confirmed COVID-19 from day 21 after receiving the first dose. All analyses excluded participants with protocol violations: the primary outcome was assessed in participants who had received two doses of vaccine or placebo, serious adverse events were assessed in all participants who had received at least one dose at the time of database lock, and rare adverse events were assessed in all participants who had received two doses and for whom all available data were verified in the case report form at the time of database lock. The trial is registered at ClinicalTrials.gov (NCT04530396). Between Sept 7 and Nov 24, 2020, 21 977 adults were randomly assigned to the vaccine group (n=16 501) or the placebo group (n=5476). 19 866 received two doses of vaccine or placebo and were included in the primary outcome anal. From 21 days after the first dose of vaccine (the day of dose 2), 16 (0·1%) of 14 964 participants in the vaccine group and 62 (1·3%) of 4902 in the placebo group were confirmed to have COVID-19; vaccine efficacy was 91·6% (95% CI 85·6-95·2). Most reported adverse events were grade 1 (7485 [94·0%] of 7966 total events). 45 (0·3%) of 16 427 participants in the vaccine group and 23 (0·4%) of 5435 participants in the placebo group had serious adverse events; none were considered assocd. with vaccination, with confirmation from the independent data monitoring committee. Four deaths were reported during the study (three [<0·1%] of 16 427 participants in the vaccine group and one [<0·1%] of 5435 participants in the placebo group), none of which were considered related to the vaccine. This interim anal. of the phase 3 trial of Gam-COVID-Vac showed 91·6% efficacy against COVID-19 and was well tolerated in a large cohort. Moscow City Health Department, Russian Direct Investment Fund, Sberbank, and RUSAL.
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    WHO. Transmission of SARS-CoV-2: implications for infection prevention precautions. https://www.who.int/news-room/commentaries/detail/transmission-of-sars-cov-2-implications-for-infection-prevention-precautions (accessed January 2020).
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    Centers for disease control and prevention. Interim clinical guidance for management of patients with confirmed coronavirus disease (COVID-19). https://www.cdc.gov/coronavirus/2019-ncov/hcp/ (accessed May 2020).
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    WHO. Target product profiles for COVID-19 vaccines , 2020. https://www.who.int/publications/m/item/who-target-product-profiles-for-covid-19-vaccines (accessed January 2020).
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    Amanat, F. K. SARS-CoV-2 vaccines: status report. Immunity 2020, 52, 583,  DOI: 10.1016/j.immuni.2020.03.007
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    SARS-CoV-2 Vaccines: Status Report
    Amanat, Fatima; Krammer, Florian
    Immunity (2020), 52 (4), 583-589CODEN: IUNIEH; ISSN:1074-7613. (Elsevier Inc.)
    A review. SARS-CoV-2, the causal agent of COVID-19, first emerged in late 2019 in China. It has since infected more than 870,000 individuals and caused more than 43,000 deaths globally. Here, we discuss therapeutic and prophylactic interventions for SARS-CoV-2 with a focus on vaccine development and its challenges. Vaccines are being rapidly developed but will likely come too late to affect the first wave of a potential pandemic. Nevertheless, crit. lessons can be learned for the development of vaccines against rapidly emerging viruses. Importantly, SARS-CoV-2 vaccines will be essential to reducing morbidity and mortality if the virus establishes itself in the population.
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    Chen, W. H.; Strych, U.; Hotez, P. J.; Bottazzi, M. E. The SARS-CoV-2 vaccine pipeline: an overview. Curr. Trop Med. Rep. 2020, 7, 61,  DOI: 10.1007/s40475-020-00201-6
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    The SARS-CoV-2 Vaccine Pipeline: an Overview
    Chen Wen-Hsiang; Strych Ulrich; Hotez Peter J; Bottazzi Maria Elena
    Current tropical medicine reports (2020), 7 (2), 61-64 ISSN:2196-3045.
    Purpose of Review: The goal of this review is to provide a timely overview on efforts to develop a vaccine for the 2019 novel coronavirus SARS-CoV-2, the causative agent of coronavirus disease (COVID-19). Recent Findings: Previous research efforts to develop a severe acute respiratory syndrome coronavirus (SARS-CoV) vaccine in the years following the 2003 pandemic have opened the door for investigators to design vaccine concepts and approaches for the COVID-19 epidemic in China. Both SARS-CoV and SARS-CoV-2 exhibit a high degree of genetic similarity and bind to the same host cell ACE2 receptor. Based on previous experience with SARS-CoV vaccines, it is expected that all COVID-19 vaccines will require careful safety evaluations for immunopotentiation that could lead to increased infectivity or eosinophilic infiltration. Besides this, a COVID-19 vaccine target product profile must address vaccinating at-risk human populations including frontline healthcare workers, individuals over the age of 60, and those with underlying and debilitating chronic conditions. Among the vaccine technologies under evaluation are whole virus vaccines, recombinant protein subunit vaccines, and nucleic acid vaccines. Summary: Each current vaccine strategy has distinct advantages and disadvantages. Therefore, it is paramount that multiple strategies be advanced quickly and then evaluated for safety and efficacy. Ultimately, the safety studies to minimize undesired immunopotentiation will become the most significant bottleneck in terms of time.
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    Leader, B.; Baca, Q. J.; Golan, D. E. Protein therapeutics: a summary and pharmacological classification. Nat. Rev. Drug Discovery 2008, 7, 21– 39,  DOI: 10.1038/nrd2399
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    Protein therapeutics: a summary and pharmacological classification
    Leader, Benjamin; Baca, Quentin J.; Golan, David E.
    Nature Reviews Drug Discovery (2008), 7 (1), 21-39CODEN: NRDDAG; ISSN:1474-1776. (Nature Publishing Group)
    A review. Once a rarely used subset of medical treatments, protein therapeutics have increased dramatically in no. and frequency of use since the introduction of the first recombinant protein therapeutic - human insulin - 25 years ago. Protein therapeutics already have a significant role in almost every field of medicine, but this role is still only in its infancy. This article overviews some of the key characteristics of protein therapeutics, summarizes the more than 130 protein therapeutics used currently and suggests a new classification of these proteins according to their pharmacol. action.
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    Suntharalingam, G.; Perry, M. R.; Ward, S.; Brett, S. J.; Panoskaltsis, N. Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412. N. Engl. J. Med. 2006, 355, 1018– 1028,  DOI: 10.1056/NEJMoa063842
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    Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412
    Suntharalingam, Ganesh; Perry, Meghan R.; Ward, Stephen; Brett, Stephen J.; Castello-Cortes, Andrew; Brunner, Michael D.; Panoskaltsis, Nicki
    New England Journal of Medicine (2006), 355 (10), 1018-1028CODEN: NEJMAG; ISSN:0028-4793. (Massachusetts Medical Society)
    Six healthy young male volunteers at a contract research organization were enrolled in the first phase 1 clin. trial of TGN1412, a novel superagonist anti-CD28 monoclonal antibody that directly stimulates T cells. Within 90 min after receiving a single i.v. dose of the drug, all six volunteers had a systemic inflammatory response characterized by a rapid induction of proinflammatory cytokines and accompanied by headache, myalgias, nausea, diarrhea, erythema, vasodilatation, and hypotension. Within 12 to 16 h after infusion, they became critically ill, with pulmonary infiltrates and lung injury, renal failure, and disseminated intravascular coagulation. Severe and unexpected depletion of lymphocytes and monocytes occurred within 24 h after infusion. All six patients were transferred to the care of the authors at an intensive care unit at a public hospital, where they received intensive cardiopulmonary support (including dialysis), high-dose methylprednisolone, and an anti-interleukin-2 receptor antagonist antibody. Prolonged cardiovascular shock and acute respiratory distress syndrome developed in two patients, who required intensive organ support for 8 and 16 days. Despite evidence of the multiple cytokine-release syndrome, all six patients survived. Documentation of the clin. course occurring over the 30 days after infusion offers insight into the systemic inflammatory response syndrome in the absence of contaminating pathogens, endotoxin, or underlying disease.
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    Wadman, M. London’s disastrous drug trial has serious side effects for research. Nature 2006, 440, 388– 389,  DOI: 10.1038/440388a
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    London's disastrous drug trial has serious side effects for research
    Wadman, Meredith
    Nature (London, United Kingdom) (2006), 440 (7083), 388-389CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)
    There is no expanded citation for this reference.
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    Huck, B. R.; Kötzner, L.; Urbahns, K. Small molecules drive big improvements in immuno-oncology therapies. Angew. Chem., Int. Ed. 2018, 57, 4412– 4428,  DOI: 10.1002/anie.201707816
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    Small Molecules Drive Big Improvements in Immuno-Oncology Therapies
    Huck, Bayard R.; Koetzner, Lisa; Urbahns, Klaus
    Angewandte Chemie, International Edition (2018), 57 (16), 4412-4428CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
    A review. Immunooncol. therapies have the potential to revolutionize the armamentarium of available cancer treatments. To further improve clin. response rates, researchers are looking for novel combination regimens, with checkpoint blockade being used as a backbone of the treatment. This Review highlights the significance of small mols. in this approach, which holds promise to provide increased benefit to cancer patients.
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    Gadek, T. R.; Burdick, D. J.; McDowell, R. S.; Stanley, M. S. Generation of an LFA-1 antagonist by the transfer of the ICAM-1 immunoregulatory epitope to a small molecule. Science 2002, 295, 1086– 1089,  DOI: 10.1126/science.295.5557.1086
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    Generation of an LFA-1 antagonist by the transfer of the ICAM-1 immunoregulatory epitope to a small molecule
    Gadek, T. R.; Burdick, D. J.; McDowell, R. S.; Stanley, M. S.; Marsters, J. C., Jr.; Paris, K. J.; Oare, D. A.; Reynolds, M. E.; Ladner, C.; Zioncheck, K. A.; Lee, W. P.; Gribling, P.; Dennis, M. S.; Skelton, N. J.; Tumas, D. B.; Clark, K. R.; Keating, S. M.; Beresini, M. H.; Tilley, J. W.; Presta, L. G.; Bodary, S. C.
    Science (Washington, DC, United States) (2002), 295 (5557), 1086-1089CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)
    The protein-protein interaction between leukocyte functional antigen-1 (LFA-1) and intercellular adhesion mol.-1 (ICAM-1) is crit. to lymphocyte and immune system function. Here, we report on the transfer of the contiguous, nonlinear epitope of ICAM-1, responsible for its assocn. with LFA-1, to a small-mol. framework. These LFA-1 antagonists bound LFA-1, blocked binding of ICAM-1, and inhibited a mixed lymphocyte reaction (MLR) with potency significantly greater than that of cyclosporine A. Furthermore, in comparison to an antibody to LFA-1, they exhibited significant anti-inflammatory effects in vivo. These results demonstrate the utility of small-mol. mimics of nonlinear protein epitopes and the protein epitopes themselves as leads in the identification of novel pharmaceutical agents.
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    Scott, D. E.; Bayly, A. R.; Abell, C.; Skidmore, J. Small molecules, big targets: drug discovery faces the protein-protein interaction challenge. Nat. Rev. Drug Discovery 2016, 15, 533– 550,  DOI: 10.1038/nrd.2016.29
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    Small molecules, big targets: drug discovery faces the protein-protein interaction challenge
    Scott, Duncan E.; Bayly, Andrew R.; Abell, Chris; Skidmore, John
    Nature Reviews Drug Discovery (2016), 15 (8), 533-550CODEN: NRDDAG; ISSN:1474-1776. (Nature Publishing Group)
    Protein-protein interactions (PPIs) are of pivotal importance in the regulation of biol. systems and are consequently implicated in the development of disease states. Recent work has begun to show that, with the right tools, certain classes of PPI can yield to the efforts of medicinal chemists to develop inhibitors, and the first PPI inhibitors have reached clin. development. In this Review, we describe the research leading to these breakthroughs and highlight the existence of groups of structurally related PPIs within the PPI target class. For each of these groups, we use examples of successful discovery efforts to illustrate the research strategies that have proved most useful.
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    Zhang, G.; Pomplun, S.; Loftis, A. R.; Loas, A.; Pentelute, B. L. Investigation of ACE2 N-terminal fragments binding to SARS-CoV-2 spike RBD. bioRxiv , June 17, 2020, ver. 1.  DOI: 10.1101/2020.03.19.999318 .
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    Han, Y.; Král, P. Computational design of ACE2-based peptide inhibitors of SARS-CoV-2. ACS Nano 2020, 14, 5143– 5147,  DOI: 10.1021/acsnano.0c02857
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    Computational design of ACE2-based peptide inhibitors of SARS-CoV-2
    Han, Yanxiao; Kral, Petr
    ACS Nano (2020), 14 (4), 5143-5147CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)
    Peptide inhibitors against the SARS-CoV-2 coronavirus, currently causing a worldwide pandemic, are designed and simulated. The inhibitors are mostly formed by two sequential self-supporting α-helixes (bundle) extd. from the protease domain (PD) of angiotensin-converting enzyme 2 (ACE2), which bind to the SARS-CoV-2 receptor binding domains. Mol. dynamics simulations revealed that the α-helical peptides maintain their secondary structure and provide a highly specific and stable binding (blocking) to SARS-CoV-2. To provide a multivalent binding to the SARS-CoV-2 receptors, many such peptides could be attached to the surfaces of nanoparticle carriers. The proposed peptide inhibitors could provide simple and efficient therapeutics against the COVID-19 disease.
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    Karoyan, P.; Vieillard, V.; Gómez-Morales, L. Human ACE2 peptide-mimics block SARS-CoV-2 pulmonary cells infection. Commun. Biol. 2021, 4, 197,  DOI: 10.1038/s42003-021-01736-8
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    Human ACE2 peptide-mimics block SARS-CoV-2 pulmonary cells infection
    Karoyan, Philippe; Vieillard, Vincent; Gomez-Morales, Luis; Odile, Estelle; Guihot, Amelie; Luyt, Charles-Edouard; Denis, Alexis; Grondin, Pascal; Lequin, Olivier
    Communications Biology (2021), 4 (1), 197CODEN: CBOIDQ; ISSN:2399-3642. (Nature Research)
    In light of the recent accumulated knowledge on SARS-CoV-2 and its mode of human cells invasion, the binding of viral spike glycoprotein to human Angiotensin Converting Enzyme 2 (hACE2) receptor plays a central role in cell entry. We designed a series of peptides mimicking the N-terminal helix of hACE2 protein which contains most of the contacting residues at the binding site, exhibiting a high helical folding propensity in aq. soln. Our best peptide-mimics are able to block SARS-CoV-2 human pulmonary cell infection with an inhibitory concn. (IC50) in the nanomolar range upon binding to the virus spike protein with high affinity. These first-in-class blocking peptide mimics represent powerful tools that might be used in prophylactic and therapeutic approaches to fight the coronavirus disease 2019 (COVID-19).
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    Curreli, F.; Victor, S. M. B.; Ahmed, S.; Drelich, A. Stapled peptides based on human angiotensin-converting enzyme 2 (ACE2) potently inhibit SARS-CoV-2 infection in vitro. mBio 2020, 11, e02451-20  DOI: 10.1128/mBio.02451-20
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    Tai, W. Identification of SARS-CoV RBD-targeting monoclonal antibodies with cross-reactive or neutralizing activity against SARS-CoV-2. Antiviral Res. 2020, 179, 104820,  DOI: 10.1016/j.antiviral.2020.104820
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    Identification of SARS-CoV RBD-targeting monoclonal antibodies with cross-reactive or neutralizing activity against SARS-CoV-2
    Tai, Wanbo; Zhang, Xiujuan; He, Yuxian; Jiang, Shibo; Du, Lanying
    Antiviral Research (2020), 179 (), 104820CODEN: ARSRDR; ISSN:0166-3542. (Elsevier B.V.)
    SARS-CoV-2-caused COVID-19 cases are growing globally, calling for developing effective therapeutics to control the current pandemic. SARS-CoV-2 and SARS-CoV recognize angiotensin-converting enzyme 2 (ACE2) receptor via the receptor-binding domain (RBD). Here, we identified six SARS-CoV RBD-specific neutralizing monoclonal antibodies (nAbs) that cross-reacted with SARS-CoV-2 RBD, two of which, 18F3 and 7B11, neutralized SARS-CoV-2 infection. 18F3 recognized conserved epitopes on SARS-CoV and SARS-CoV-2 RBDs, whereas 7B11 recognized epitopes on SARS-CoV RBD not fully conserved in SARS-CoV-2 RBD. The 18F3-recognizing epitopes on RBD did not overlap with the ACE2-binding sites, whereas those recognized by 7B11 were close to the ACE2-binding sites, explaining why 7B11 could, but 18F3 could not, block SARS-CoV or SARS-CoV-2 RBD binding to ACE2 receptor. Our study provides an alternative approach to prevent SARS-CoV-2 infection using anti-SARS-CoV nAbs.
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    De Vries, R. D.; Schmitz, K. S.; Bovier, F. T. Intranasal fusion inhibitory lipopeptide prevents direct contact SARS-CoV-2 transmission in ferrets. bioRxiv , November 5, 2020, ver. 1.  DOI: 10.1101/2020.11.04.361154 .
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    Tai, W.; He, L.; Zhang, X.; Pu, J.; Voronin, D.; Jiang, S.; Zhou, Y.; Du, L. Characterization of the receptor-binding domain (RBD) of 2019 novel coronavirus: implication for development of RBD protein as a viral attachment inhibitor and vaccine. Cell. Mol. Immunol. 2020, 17, 613– 620,  DOI: 10.1038/s41423-020-0400-4
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    Characterization of the receptor-binding domain (RBD) of 2019 novel coronavirus: implication for development of RBD protein as a viral attachment inhibitor and vaccine
    Tai, Wanbo; He, Lei; Zhang, Xiujuan; Pu, Jing; Voronin, Denis; Jiang, Shibo; Zhou, Yusen; Du, Lanying
    Cellular & Molecular Immunology (2020), 17 (6), 613-620CODEN: CMIEAO; ISSN:1672-7681. (Nature Research)
    The outbreak of Coronavirus Disease 2019 (COVID-19) has posed a serious threat to global public health, calling for the development of safe and effective prophylactics and therapeutics against infection of its causative agent, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), also known as 2019 novel coronavirus (2019-nCoV). The CoV spike (S) protein plays the most important roles in viral attachment, fusion and entry, and serves as a target for development of antibodies, entry inhibitors and vaccines. Here, we identified the receptor-binding domain (RBD) in SARS-CoV-2 S protein and found that the RBD protein bound strongly to human and bat angiotensin-converting enzyme 2 (ACE2) receptors. SARS-CoV-2 RBD exhibited significantly higher binding affinity to ACE2 receptor than SARS-CoV RBD and could block the binding and, hence, attachment of SARS-CoV-2 RBD and SARS-CoV RBD to ACE2-expressing cells, thus inhibiting their infection to host cells. SARS-CoV RBD-specific antibodies could cross-react with SARS-CoV-2 RBD protein, and SARS-CoV RBD-induced antisera could cross-neutralize SARS-CoV-2, suggesting the potential to develop SARS-CoV RBD-based vaccines for prevention of SARS-CoV-2 and SARS-CoV infection.
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    Sun, C.; Chen, L.; Yang, J. SARS-CoV-2 and SARS-CoV spike-RBD structure and receptor binding comparison and potential implications on neutralizing antibody and vaccine development. bioRxiv , February 20, 2020, ver. 1.  DOI: 10.1101/2020.02.16.951723 .
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    Xia, S.; Yan, L.; Xu, W.; Agrawal, A. S.; Algaissi, A.; Tseng, C. K.; Wang, Q.; Du, L.; Tan, W.; Wilson, I. A.; Jiang, S.; Yang, B.; Lu, L. A pan-coronavirus fusion inhibitor targeting the HR1mdomain of human coronavirus spike. Sci. Adv. 2019, 5, eaav4580  DOI: 10.1126/sciadv.aav4580
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    Rathod, S. B.; Prajapati, P. B.; Punjabi, L. B.; Prajapati, K. N.; Chauhan, N.; Mansuri, M. F. Peptide modelling and screening against human ACE2 and spike glycoprotein RBD of SARS CoV 2. In Silico Pharmacol. 2020, 8, 3,  DOI: 10.1007/s40203-020-00055-w
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    Peptide modelling and screening against human ACE2 and spike glycoprotein RBD of SARS-CoV-2
    Rathod Shravan B; Prajapati Pravin B; Prajapati Kuntal N; Punjabi Lata B; Chauhan Neha; Mansuri Mohmedyasin F
    In silico pharmacology (2020), 8 (1), 3 ISSN:2193-9616.
    Outbreak of Coronavirus Disease 2019 (COVID-19) has become a great challenge for scientific community globally. Virus enters cell through spike glycoprotein fusion with ACE2 (Angiotensin-Converting Enzyme 2) human receptor. Hence, spike glycoprotein of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a potential target for diagnostics, vaccines, and antibodies. Also, virus entry can be prevented by blocking ACE2 thus, ACE2 can be considered potential target for therapeutics. As being highly specific, safe and efficacious, peptides hold their place in therapeutics. In present study, we retrieved sequence of 70 peptides from Antiviral Peptide Database (AVPdb), modelled them using 3D structure predicting web tool and docked them with receptor binding domain (RBD) of spike protein and human host receptor ACE2 using peptide-protein docking. It was observed that peptides have more affinity towards ACE2 in comparison with spike RBD. Interestingly it was noticed that most of the peptides bind to RBM (residue binding motif) which is responsible for ACE2 binding at the interface of RBD while, for ACE2, peptides prefer to bind the core cavity rather than RBD binding interface. To further investigate how peptides at the interface of RBD or ACE2 alter the binding between RBD and ACE2, protein-protein docking of RBD and ACE2 with and without peptides was performed. Peptides, AVP0671 at RBD and AVP1244 at ACE2 interfaces significantly reduce the binding affinity and change the orientation of RBD and ACE2 binding. This finding suggests that peptides can be used as a drug to inhibit virus entry in cells to stop COVID-19 pandemic in the future after experimental evidences.
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    Watson, A.; Ferreira, L.; Hwang, P.; Xu, J.; Stroud, R. Peptide antidotes to SARS-CoV-2 (COVID-19). bioRxiv , August 6, 2020, ver. 1.  DOI: 10.1101/2020.08.06.238915 .
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    Singh, A.; Thakur, M.; Sharma, L. K.; Chandra, K. Designing a multi epitope peptide based vaccine against SARS CoV 2. Sci. Rep. 2020, 10, 16219,  DOI: 10.1038/s41598-020-73371-y
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    Designing a multi-epitope peptide based vaccine against SARS-CoV-2
    Singh, Abhishek; Thakur, Mukesh; Sharma, Lalit Kumar; Chandra, Kailash
    Scientific Reports (2020), 10 (1), 16219CODEN: SRCEC3; ISSN:2045-2322. (Nature Research)
    COVID-19 pandemic has resulted in 16,114,449 cases with 646,641 deaths from the 217 countries, or territories as on July 27th 2020. Due to multifaceted issues and challenges in the implementation of the safety and preventive measures, inconsistent coordination between societies-governments and most importantly lack of specific vaccine to SARS-CoV-2, the spread of the virus that initially emerged at Wuhan is still uprising after taking a heavy toll on human life. In the present study, we mapped immunogenic epitopes present on the four structural proteins of SARS-CoV-2 and we designed a multi-epitope peptide based vaccine that, demonstrated a high immunogenic response with a vast application on world's human population. On codon optimization and in-silico cloning, we found that candidate vaccine showed high expression in E. coli and immune simulation resulted in inducing a high level of both B-cell and T-cell mediated immunity. The results predicted that exposure of vaccine by administrating three injections significantly subsidized the antigen growth in the system. The proposed candidate vaccine found promising by yielding desired results and hence, should be validated by practical experimentations for its functioning and efficacy to neutralize SARS-CoV-2.
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    Molina, R.; Oliva, B.; Fernandez-Fuentes, N. A collection of designed peptides to target SARS-Cov-2 – ACE2 interaction: PepI-Covid19 database. bioRxiv , April 29, 2020, ver. 1.  DOI: 10.1101/2020.04.28.051789 .
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    Zhao, H.; To, K. K. W.; Sze, K. H.; Yung, T. T.; Bian, M.; Lam, H.; Yeung, M. L.; Li, C.; Chu, H.; Yuen, K. Y. A broad-spectrum virus- and host-targeting peptide against respiratory viruses including influenza virus and SARS-CoV-2. Nat. Commun. 2020, 11, 4252,  DOI: 10.1038/s41467-020-17986-9
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    A broad-spectrum virus- and host-targeting peptide against respiratory viruses including influenza virus and SARS-CoV-2
    Zhao, Hanjun; To, Kelvin K. W.; Sze, Kong-Hung; Yung, Timothy Tin-Mong; Bian, Mingjie; Lam, Hoiyan; Yeung, Man Lung; Li, Cun; Chu, Hin; Yuen, Kwok-Yung
    Nature Communications (2020), 11 (1), 4252CODEN: NCAOBW; ISSN:2041-1723. (Nature Research)
    The 2019 novel respiratory virus (SARS-CoV-2) causes COVID-19 with rapid global socioeconomic disruptions and disease burden to healthcare. The COVID-19 and previous emerging virus outbreaks highlight the urgent need for broad-spectrum antivirals. A defensin-like peptide P9R exhibited potent antiviral activity against pH-dependent viruses that require endosomal acidification for virus infection, including the enveloped pandemic A(H1N1)pdm09 virus, avian influenza A(H7N9) virus, coronaviruses (SARS-CoV-2, MERS-CoV and SARS-CoV), and the non-enveloped rhinovirus. P9R can significantly protect mice from lethal challenge by A(H1N1)pdm09 virus and shows low possibility to cause drug-resistant virus. Mechanistic studies indicate that the antiviral activity of P9R depends on the direct binding to viruses and the inhibition of virus-host endosomal acidification, which provides a proof of concept that virus-binding alk. peptides can broadly inhibit pH-dependent viruses. These results suggest that the dual-functional virus- and host-targeting P9R can be a promising candidate for combating pH-dependent respiratory viruses.
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    Han, D. P.; Penn-Nicholson, A.; Cho, M. W. Identification of critical determinants on ACE2 for SARS-CoV entry and development of a potent entry inhibitor. Virology 2006, 350 (1), 15– 25,  DOI: 10.1016/j.virol.2006.01.029
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    Identification of critical determinants on ACE2 for SARS-CoV entry and development of a potent entry inhibitor
    Han, Dong P.; Penn-Nicholson, Adam; Cho, Michael W.
    Virology (2006), 350 (1), 15-25CODEN: VIRLAX; ISSN:0042-6822. (Elsevier)
    Severe acute respiratory syndrome (SARS) is caused by a novel coronavirus, SARS-CoV. Virus entry into cells is mediated through interactions between spike (S) glycoprotein and angiotensin-converting enzyme 2 (ACE2). Alanine scanning mutagenesis anal. was performed to identify determinants on ACE2 crit. for SARS-CoV infection. Results indicated that charged amino acids between residues 22 and 57 were important, K26 and D30, in particular. Peptides representing various regions of ACE2 crit. for virus infection were chem. synthesized and evaluated for antiviral activity. Two peptides (a.a. 22-44 and 22-57) exhibited a modest antiviral activity with IC50 of about 50 μM and 6 μM, resp. One peptide comprised of two discontinuous segments of ACE2 (a.a. 22-44 and 351-357) artificially linked together by glycine, exhibited a potent antiviral activity with IC50 of about 0.1 μM. This novel peptide is a promising candidate as a therapeutic agent against this deadly emerging pathogen.
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    Shang, J.; Ye, G.; Shi, K.; Wan, Y.; Luo, C.; Aihara, H.; Geng, Q.; Auerbach, A.; Li, F. Structural basis of receptor recognition by SARS-CoV-2. Nature 2020, 581, 221– 224,  DOI: 10.1038/s41586-020-2179-y
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    Structural basis of receptor recognition by SARS-CoV-2
    Shang, Jian; Ye, Gang; Shi, Ke; Wan, Yushun; Luo, Chuming; Aihara, Hideki; Geng, Qibin; Auerbach, Ashley; Li, Fang
    Nature (London, United Kingdom) (2020), 581 (7807), 221-224CODEN: NATUAS; ISSN:0028-0836. (Nature Research)
    Abstr.: A novel severe acute respiratory syndrome (SARS)-like coronavirus (SARS-CoV-2) recently emerged and is rapidly spreading in humans, causing COVID-191,2. A key to tackling this pandemic is to understand the receptor recognition mechanism of the virus, which regulates its infectivity, pathogenesis and host range. SARS-CoV-2 and SARS-CoV recognize the same receptor-angiotensin-converting enzyme 2 (ACE2)-in humans3,4. Here we detd. the crystal structure of the receptor-binding domain (RBD) of the spike protein of SARS-CoV-2 (engineered to facilitate crystn.) in complex with ACE2. In comparison with the SARS-CoV RBD, an ACE2-binding ridge in SARS-CoV-2 RBD has a more compact conformation; moreover, several residue changes in the SARS-CoV-2 RBD stabilize two virus-binding hotspots at the RBD-ACE2 interface. These structural features of SARS-CoV-2 RBD increase its ACE2-binding affinity. Addnl., we show that RaTG13, a bat coronavirus that is closely related to SARS-CoV-2, also uses human ACE2 as its receptor. The differences among SARS-CoV-2, SARS-CoV and RaTG13 in ACE2 recognition shed light on the potential animal-to-human transmission of SARS-CoV-2. This study provides guidance for intervention strategies that target receptor recognition by SARS-CoV-2.
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    Zhou, T.; Tsybovsky, Y.; Gorman, J.; Rapp, M.; Cerutti, G. Cryo-EM structures of SARS-CoV-2 spike without and with ACE2 reveal a pH-dependent switch to mediate endosomal positioning of receptor-binding domains. Cell Host Microbe 2020, 28 (6), 867– 879,  DOI: 10.1016/j.chom.2020.11.004
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    50
    Cryo-EM Structures of SARS-CoV-2 Spike without and with ACE2 Reveal a pH-Dependent Switch to Mediate Endosomal Positioning of Receptor-Binding Domains
    Zhou, Tongqing; Tsybovsky, Yaroslav; Gorman, Jason; Rapp, Micah; Cerutti, Gabriele; Chuang, Gwo-Yu; Katsamba, Phinikoula S.; Sampson, Jared M.; Schon, Arne; Bimela, Jude; Boyington, Jeffrey C.; Nazzari, Alexandra; Olia, Adam S.; Shi, Wei; Sastry, Mallika; Stephens, Tyler; Stuckey, Jonathan; Teng, I-Ting; Wang, Pengfei; Wang, Shuishu; Zhang, Baoshan; Friesner, Richard A.; Ho, David D.; Mascola, John R.; Shapiro, Lawrence; Kwong, Peter D.
    Cell Host & Microbe (2020), 28 (6), 867-879.e5CODEN: CHMECB; ISSN:1931-3128. (Elsevier Inc.)
    The SARS-CoV-2 spike employs mobile receptor-binding domains (RBDs) to engage the human ACE2 receptor and to facilitate virus entry, which can occur through low-pH-endosomal pathways. To understand how ACE2 binding and low pH affect spike conformation, we detd. cryo-electron microscopy structures-at serol. and endosomal pH-delineating spike recognition of up to three ACE2 mols. RBDs freely adopted "up" conformations required for ACE2 interaction, primarily through RBD movement combined with smaller alterations in neighboring domains. In the absence of ACE2, single-RBD-up conformations dominated at pH 5.5, resolving into a solitary all-down conformation at lower pH. Notably, a pH-dependent refolding region (residues 824-858) at the spike-interdomain interface displayed dramatic structural rearrangements and mediated RBD positioning through coordinated movements of the entire trimer apex. These structures provide a foundation for understanding prefusion-spike mechanics governing endosomal entry; we suggest that the low pH all-down conformation potentially facilitates immune evasion from RBD-up binding antibody.
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    Lan, J.; Ge, J.; Yu, J.; Shan, S.; Zhou, H.; Fan, S.; Zhang, Q.; Shi, X.; Wang, Q.; Zhang, L.; Wang, X. Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor. Nature 2020, 581, 215– 220,  DOI: 10.1038/s41586-020-2180-5
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    51
    Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor
    Lan, Jun; Ge, Jiwan; Yu, Jinfang; Shan, Sisi; Zhou, Huan; Fan, Shilong; Zhang, Qi; Shi, Xuanling; Wang, Qisheng; Zhang, Linqi; Wang, Xinquan
    Nature (London, United Kingdom) (2020), 581 (7807), 215-220CODEN: NATUAS; ISSN:0028-0836. (Nature Research)
    Abstr.: A new and highly pathogenic coronavirus (severe acute respiratory syndrome coronavirus-2, SARS-CoV-2) caused an outbreak in Wuhan city, Hubei province, China, starting from Dec. 2019 that quickly spread nationwide and to other countries around the world1-3. Here, to better understand the initial step of infection at an at. level, we detd. the crystal structure of the receptor-binding domain (RBD) of the spike protein of SARS-CoV-2 bound to the cell receptor ACE2. The overall ACE2-binding mode of the SARS-CoV-2 RBD is nearly identical to that of the SARS-CoV RBD, which also uses ACE2 as the cell receptor4. Structural anal. identified residues in the SARS-CoV-2 RBD that are essential for ACE2 binding, the majority of which either are highly conserved or share similar side chain properties with those in the SARS-CoV RBD. Such similarity in structure and sequence strongly indicate convergent evolution between the SARS-CoV-2 and SARS-CoV RBDs for improved binding to ACE2, although SARS-CoV-2 does not cluster within SARS and SARS-related coronaviruses1-3,5. The epitopes of two SARS-CoV antibodies that target the RBD are also analyzed for binding to the SARS-CoV-2 RBD, providing insights into the future identification of cross-reactive antibodies.
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  52. 52
    Sadremomtaz, A.; Ali, A. M.; Jouyandeh, F.; Balalaie, S.; Navari, R. Molecular docking, synthesis and biological evaluation of vascular endothelial growth factor (VEGF) B based peptide as antiangiogenic agent targeting the second domain of the vascular endothelial growth factor receptor 1 (VEGFR1D2) for anticancer application. Sig. Transduct. Target Ther. 2020, 5, 76,  DOI: 10.1038/s41392-020-0177-z
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    Sadremomtaz, A.; Mansouri, K.; Alemzadeh, G.; Safa, M.; Rastaghi, A. E.; Asghari, S. M. Dual blockade of VEGFR1 and VEGFR2 by a novel peptide abrogates VEGF driven angiogenesis, tumor growth, and metastasis through PI3K/ AKT and MAPK/ERK1/2 pathway. Biochim. Biophys. Acta, Gen. Subj. 2018, 1862, 2688– 2700,  DOI: 10.1016/j.bbagen.2018.08.013
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    53
    Dual blockade of VEGFR1 and VEGFR2 by a novel peptide abrogates VEGF-driven angiogenesis, tumor growth, and metastasis through PI3K/AKT and MAPK/ERK1/2 pathway
    Sadremomtaz, Afsaneh; Mansouri, Kamran; Alemzadeh, Golnaz; Safa, Majid; Rastaghi, Ahmadreza Esmaeili; Asghari, S. Mohsen
    Biochimica et Biophysica Acta, General Subjects (2018), 1862 (12), 2688-2700CODEN: BBGSB3; ISSN:0304-4165. (Elsevier B.V.)
    Neutralization of vascular endothelial growth factor receptor 1 (VEGFR1) and/or VEGFR2 is a widely used means of inhibiting tumor angiogenesis. Based on the complex X-ray structures of VEGFA/VEGFR1, VEGFA/VEGFR2, and VEGFB/VEGFR1, a peptide (referred to as VGB) was designed to simultaneously bind to VEGFR1 and VEGFR2, and binding, antiangiogenic and antitumor properties of the peptide was investigated in vitro. VGB bound to both VEGFR1 and VEGFR2 in human umbilical vein endothelial cells (HUVECs), and inhibited the proliferation of HUVECs, 4 T1 mammary carcinoma tumor (MCT) cells in human umbilical vein endothelial cells (HUVECs) and 4T1 mammary carcinoma tumor (MCT) cells, and inhibited the proliferation of HUVE, 4T1 MCT, and U87 glioblastoma cells. Through abrogation of AKT and ERK1/2 phosphorylation, VEGFA-stimulated proliferation, migration, and two- and three-dimensional tube formation in HUVECs were inhibited more potently by VGB than by bevacizumab. In a murine 4 T1 MCT model, VGB strongly inhibited tumor growth without causing wt. loss, accompanied by inhibition of AKT and ERK1/2 phosphorylation, a significant decrease in tumor cell proliferation (Ki-67 expression), angiogenesis (CD31 and CD34 expression), an increase in apoptosis index (increased TUNEL staining and p53 expression and decreased Bcl-2 expression), and the suppression of systematic spreading of the tumor (reduced NF-κB and MMP-9 and increased E-cadherin expression). The dual specificity of VGB for VEGFR1 and VEGFR2, through which the PI3K/AKT and MAPK/ERK1/2 signaling pathways can be abrogated and, subsequently, angiogenesis, tumor growth, and metastasis are inhibited. This study demonstrated that simultaneous blockade of VEGFR1 and VEGFR2 downstream cascades is an effective means for treatment of various angiogenic disorders, esp. cancer.
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    Sadremomtaz, A.; Kobarfard, F.; Mansouri, K.; Mirzanejad, L.; Asghari, S. M. Suppression of migratory and metastatic pathways via blocking VEGFR1 and VEGFR2. J. Recept. Signal Transduction Res. 2018, 38, 432– 441,  DOI: 10.1080/10799893.2019.1567785
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    54
    Suppression of migratory and metastatic pathways via blocking VEGFR1 and VEGFR2
    Sadremomtaz Afsaneh; Mirzanejad Laleh; Asghari S Mohsen; Kobarfard Farzad; Mansouri Kamran
    Journal of receptor and signal transduction research (2018), 38 (5-6), 432-441 ISSN:.
    BACKGROUND: Vascular endothelial growth factor (VEGF) A and B are endothelial cell mitogens whose ligation to VEGFR1/VEGFR2 drives tumor angiogenesis and metastasis, and epithelial-mesenchymal transition (EMT). Blockade of these signaling axes could be obtained by disturbing the interactions between VEGFA and/or VEGFB with VEGFR1 and/or VEGFR2. METHODS: A 14-mer peptide (VGB) that recognizes both VEGFR1 and VEGFR2 were investigated for its inhibitory effects on the VEGF-induced proliferation and migration using MTT and scratch assay, respectively. Downstream signaling pathways were also assessed by quantitative estimation of gene and protein expression using real-time PCR and immunohistochemistry (IHC). RESULTS: We investigated the inhibitory effects of VGB on downstream mediators of metastasis, including epithelial-cadherin (E-cadherin), matrix metalloprotease-9 (MMP-9), cancer myelocytomatosis (c-Myc), and nuclear factor-κβ (NF-κβ), and migration, comprising focal adhesion kinase (FAK) and its substrate Paxilin. VGB inhibited the VEGF-induced proliferation of human umbilical vein endothelial cells (HUVECs), 4T1 and U87 cells in a time- and dose-dependent manner and migration of HUVECs. Based on IHC analyses, treatment of 4T1 mammary carcinoma tumor with VGB led to the suppression of p-AKT, p-ERK1/2, MMP-9, NF-κβ, and activation of E-cadherin compared with PBS-treated controls. Moreover, quantitative real-time PCR analyses of VGB-treated tumors revealed the reduced expression level of FAK, Paxilin, NF-κβ, MMP-9, c-Myc, and increased expression level of E-cadherin compared to PBS-treated controls. CONCLUSIONS: Our results demonstrated that simultaneous blockade of VEGFR1/VEGFR2 is an effective strategy to fight solid tumors by targeting a wider range of mediators involved in tumor angiogenesis, growth, and metastasis.
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    Abraham, M. J.; Murtola, T.; Schulz, R.; Pall, S.; Smith, J. C.; Hess, B.; Lindahl, E. GROMACS: High performance molecular simulations through multi-level parallelism from laptops to supercomputers. SoftwareX. 2015, 1 (2), 19– 25,  DOI: 10.1016/j.softx.2015.06.001
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    Jo, S.; Kim, T.; Iyer, V. G.; Im, W. CHARMM-GUI: a web-based graphical user interface for CHARMM. J. Comput. Chem. 2008, 29, 1859– 1865,  DOI: 10.1002/jcc.20945
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    CHARMM-GUI: a web-based graphical user interface for CHARMM
    Jo, Sunhwan; Kim, Taehoon; Iyer, Vidyashankara G.; Im, Wonpil
    Journal of Computational Chemistry (2008), 29 (11), 1859-1865CODEN: JCCHDD; ISSN:0192-8651. (John Wiley & Sons, Inc.)
    CHARMM is an academic research program used widely for macromol. mechanics and dynamics with versatile anal. and manipulation tools of at. coordinates and dynamics trajectories. CHARMM-GUI, http://www.charmm-gui.org, has been developed to provide a web-based graphical user interface to generate various input files and mol. systems to facilitate and standardize the usage of common and advanced simulation techniques in CHARMM. The web environment provides an ideal platform to build and validate a mol. model system in an interactive fashion such that, if a problem is found through visual inspection, one can go back to the previous setup and regenerate the whole system again. In this article, we describe the currently available functional modules of CHARMM-GUI Input Generator that form a basis for the advanced simulation techniques. Future directions of the CHARMM-GUI development project are also discussed briefly together with other features in the CHARMM-GUI website, such as Archive and Movie Gallery.
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    Gowers, R. J.; Linke, M.; Barnoud, J.; Reddy, T. J. E.; Melo, M. N.; Seyler, S. MDanalysis: a python package for the rapid analysis of molecular dynamics simulations. Proceedings of the 15th python in science conference 2016, 98– 105,  DOI: 10.25080/Majora-629e541a-00e
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    Salentin, S.; Schreiber, S.; Haupt, V. J.; Adasme, M. F.; Schroeder, M. PLIP: fully automated protein–ligand interaction profiler. Nucleic Acids Res. 2015, 43, W443– W447,  DOI: 10.1093/nar/gkv315
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    PLIP: fully automated protein-ligand interaction profiler
    Salentin, Sebastian; Schreiber, Sven; Haupt, V. Joachim; Adasme, Melissa F.; Schroeder, Michael
    Nucleic Acids Research (2015), 43 (W1), W443-W447CODEN: NARHAD; ISSN:0305-1048. (Oxford University Press)
    The characterization of interactions in protein-ligand complexes is essential for research in structural bioinformatics, drug discovery and biol. However, comprehensive tools are not freely available to the research community. Here, we present the protein-ligand interaction profiler (PLIP), a novel web service for fully automated detection and visualization of relevant non-covalent protein-ligand contacts in 3D structures, freely available at projects.biotec.tu-dresden.de/plip-web. The input is either a Protein Data Bank structure, a protein or ligand name, or a custom protein-ligand complex (e.g. from docking). In contrast to other tools, the rule-based PLIP algorithm does not require any structure prepn. It returns a list of detected interactions on single atom level, covering seven interaction types (hydrogen bonds, hydrophobic contacts, pi-stacking, pi-cation interactions, salt bridges, water bridges and halogen bonds). PLIP stands out by offering publication-ready images, PyMOL sesions files to generate custom images and parsable result files to facilitate successive data processing. The full python source code is available for download on the website. PLIP's command-line mode allows for high-throughput interaction profiling.
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    Kayikci, M.; Venkatakrishnan, A. J.; Scott-Brown, J. Visualization and analysis of non-covalent contacts using the protein contacts atlas. Nat. Struct. Mol. Biol. 2018, 25, 185– 194,  DOI: 10.1038/s41594-017-0019-z
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    Visualization and analysis of non-covalent contacts using the Protein Contacts Atlas
    Kayikci, Melis; Venkatakrishnan, A. J.; Scott-Brown, James; Ravarani, Charles N. J.; Flock, Tilman; Babu, M. Madan
    Nature Structural & Molecular Biology (2018), 25 (2), 185-194CODEN: NSMBCU; ISSN:1545-9993. (Nature Research)
    Visualizations of biomol. structures empower us to gain insights into biol. functions, generate testable hypotheses, and communicate biol. concepts. Typical visualizations (such as ball and stick) primarily depict covalent bonds. In contrast, non-covalent contacts between atoms, which govern normal physiol., pathogenesis, and drug action, are seldom visualized. We present the Protein Contacts Atlas, an interactive resource of non-covalent contacts from over 100,000 PDB crystal structures. We developed multiple representations for visualization and anal. of non-covalent contacts at different scales of organization: atoms, residues, secondary structure, subunits, and entire complexes. The Protein Contacts Atlas enables researchers from different disciplines to investigate diverse questions in the framework of non-covalent contacts, including the interpretation of allostery, disease mutations and polymorphisms, by exploring individual subunits, interfaces, and protein-ligand contacts and by mapping external information. The Protein Contacts Atlas is available at http://www.mrc-lmb.cam.ac.uk/pca/ and also through PDBe.
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    Azad, T.; Singaravelu, R.; Taha, Z.; Boulton, S. Nanoluciferase complementation-based biosensor reveals the importance of N- linked glycosylation of SARS-CoV-2 spike for viral entry. Mol. Ther. 2021, 29, 1984,  DOI: 10.1016/j.ymthe.2021.02.007
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    Nanoluciferase complementation-based bioreporter reveals the importance of N-linked glycosylation of SARS-CoV-2 S for viral entry
    Azad, Taha; Singaravelu, Ragunath; Taha, Zaid; Jamieson, Taylor R.; Boulton, Stephen; Crupi, Mathieu J. F.; Martin, Nikolas T.; Brown, Emily E. F.; Poutou, Joanna; Ghahremani, Mina; Pelin, Adrian; Nouri, Kazem; Rezaei, Reza; Marshall, Christopher Boyd; Enomoto, Masahiro; Arulanandam, Rozanne; Alluqmani, Nouf; Samson, Reuben; Gingras, Anne-Claude; Cameron, D. William; Greer, Peter A.; Ilkow, Carolina S.; Diallo, Jean-Simon; Bell, John C.
    Molecular Therapy (2021), 29 (6), 1984-2000CODEN: MTOHCK; ISSN:1525-0024. (Cell Press)
    The ongoing COVID-19 pandemic has highlighted the immediate need for the development of antiviral therapeutics targeting different stages of the SARS-CoV-2 life cycle. We developed a bioluminescence-based bioreporter to interrogate the interaction between the SARS-CoV-2 viral spike (S) protein and its host entry receptor, angiotensin-converting enzyme 2 (ACE2). The bioreporter assay is based on a nanoluciferase complementation reporter, composed of two subunits, large BiT and small BiT, fused to the S receptor-binding domain (RBD) of the SARS-CoV-2 S protein and ACE2 ectodomain, resp. Using this bioreporter, we uncovered crit. host and viral determinants of the interaction, including a role for glycosylation of asparagine residues within the RBD in mediating successful viral entry. We also demonstrate the importance of N-linked glycosylation to the RBD's antigenicity and immunogenicity. Our study demonstrates the versatility of our bioreporter in mapping key residues mediating viral entry as well as screening inhibitors of the ACE2-RBD interaction. Our findings point toward targeting RBD glycosylation for therapeutic and vaccine strategies against SARS-CoV-2.
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    Spiliotopoulos, D.; Kastritis, P. L.; Melquiond, A. S.; Bonvin, A. M.; Musco, G.; Rocchia, W.; Spitaleri, A. dMM-PBSA: A new HADDOCK scoring function for protein-peptide docking. Front Mol. Biosci. 2016, 3, 46,  DOI: 10.3389/fmolb.2016.00046
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    dMM-PBSA: a new HADDOCK scoring function for protein-peptide docking
    Spiliotopoulos, Dimitrios; Kastritis, Panagiotis L.; Melquiond, Adrien S. J.; Bonvin, Alexandre M. J. J.; Musco, Giovanna; Rocchia, Walter; Spitaleri, Andrea
    Frontiers in Molecular Biosciences (2016), 3 (), 46/1-46/13CODEN: FMBRBS; ISSN:2296-889X. (Frontiers Media S.A.)
    Mol.-docking programs coupled with suitable scoring functions are now established and very useful tools enabling computational chemists to rapidly screen large chem. databases and thereby to identify promising candidate compds. for further exptl. processing. In a broader scenario, predicting binding affinity is one of the most crit. and challenging components of computer-aided structure-based drug design. The development of a mol. docking scoring function which in principle could combine both features, namely ranking putative poses and predicting complex affinity, would be of paramount importance. Here, we systematically investigated the performance of the MM-PBSA approach, using two different Poisson-Boltzmann solvers (APBS and DelPhi), in the currently rising field of protein-peptide interactions (PPIs), identifying the correct binding conformations of 19 different protein-peptide complexes and predicting their binding free energies. First, we scored the decoy structures from HADDOCK calcn. via the MM-PBSA approach in order to assess the capability of retrieving near-native poses in the best-scoring clusters and of evaluating the corresponding free energies of binding. MM-PBSA behaves well in finding the poses corresponding to the lowest binding free energy. In order to improve the MM-PBSA-based scoring function, we dampened the MM-PBSA solvation and coulombic terms by 0.2, as proposed in the HADDOCK score and LIE approaches.
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    Li, W.; Zhang, C.; Sui, J.; Kuhn, J. H.; Moore, M. J.; Luo, S.; Wong, S. K.; Huang, I. C.; Xu, K.; Vasilieva, N.; Murakami, A.; He, Y.; Marasco, W. A.; Guan, Y.; Choe, H.; Farzan, M. Receptor and viral determinants of SARS-coronavirus adaptation to human ACE2. EMBO J. 2005, 24, 1634– 1643,  DOI: 10.1038/sj.emboj.7600640
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    Receptor and viral determinants of SARS-coronavirus adaptation to human ACE2
    Li, Wenhui; Zhang, Chengsheng; Sui, Jianhua; Kuhn, Jens H.; Moore, Michael J.; Luo, Shiwen; Wong, Swee-Kee; Huang, I-Chueh; Xu, Keming; Vasilieva, Natalya; Murakami, Akikazu; He, Yaqing; Marasco, Wayne A.; Guan, Yi; Choe, Hyeryun; Farzan, Michael
    EMBO Journal (2005), 24 (8), 1634-1643CODEN: EMJODG; ISSN:0261-4189. (Nature Publishing Group)
    Human angiotensin-converting enzyme 2 (ACE2) is a functional receptor for SARS coronavirus (SARS-CoV). Here we identify the SARS-CoV spike (S)-protein-binding site on ACE2. We also compare S proteins of SARS-CoV isolated during the 2002-2003 SARS outbreak and during the much less severe 2003-2004 outbreak, and from palm civets, a possible source of SARS-CoV found in humans. All three S proteins bound to and utilized palm-civet ACE2 efficiently, but the latter two S proteins utilized human ACE2 markedly less efficiently than did the S protein obtained during the earlier human outbreak. The lower affinity of these S proteins could be complemented by altering specific residues within the S-protein-binding site of human ACE2 to those of civet ACE2, or by altering S-protein residues 479 and 487 to residues conserved during the 2002-2003 outbreak. Collectively, these data describe mol. interactions important to the adaptation of SARS-CoV to human cells, and provide insight into the severity of the 2002-2003 SARS epidemic.
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    Elbe, S.; Buckland-Merrett, G. Data, disease and diplomacy: GISAID’s innovative contribution to global health. Global Challenges 2017, 1, 33,  DOI: 10.1002/gch2.1018
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    Data, disease and diplomacy: GISAID's innovative contribution to global health
    Elbe Stefan; Buckland-Merrett Gemma
    Global challenges (Hoboken, NJ) (2017), 1 (1), 33-46 ISSN:.
    The international sharing of virus data is critical for protecting populations against lethal infectious disease outbreaks. Scientists must rapidly share information to assess the nature of the threat and develop new medical countermeasures. Governments need the data to trace the extent of the outbreak, initiate public health responses, and coordinate access to medicines and vaccines. Recent outbreaks suggest, however, that the sharing of such data cannot be taken for granted - making the timely international exchange of virus data a vital global challenge. This article undertakes the first analysis of the Global Initiative on Sharing All Influenza Data as an innovative policy effort to promote the international sharing of genetic and associated influenza virus data. Based on more than 20 semi-structured interviews conducted with key informants in the international community, coupled with analysis of a wide range of primary and secondary sources, the article finds that the Global Initiative on Sharing All Influenza Data contributes to global health in at least five ways: (1) collating the most complete repository of high-quality influenza data in the world; (2) facilitating the rapid sharing of potentially pandemic virus information during recent outbreaks; (3) supporting the World Health Organization's biannual seasonal flu vaccine strain selection process; (4) developing informal mechanisms for conflict resolution around the sharing of virus data; and (5) building greater trust with several countries key to global pandemic preparedness.
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    Baskaran, K.; Duarte, J. M.; Biyani, N.; Bliven, S.; Capitani, G. A PDB-wide, evolution-based assessment of protein-protein interfaces. BMC Struct. Biol. 2014, 14, 1422,  DOI: 10.1186/s12900-014-0022-0
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    Amaral, M.; Kokh, D. B.; Bomke, J.; Wegener, A.; Buchstaller, H. P.; Eggenweiler, H. M. Protein conformational flexibility modulates kinetics and thermodynamics of drug binding. Nat. Commun. 2017, 8, 2276,  DOI: 10.1038/s41467-017-02258-w
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    Protein conformational flexibility modulates kinetics and thermodynamics of drug binding
    Amaral M; Matias P; Amaral M; Wegener A; Frech M; Amaral M; Kokh D B; Wade R C; Bomke J; Buchstaller H P; Eggenweiler H M; Matias P; Sirrenberg C; Wade R C; Wade R C
    Nature communications (2017), 8 (1), 2276 ISSN:.
    Structure-based drug design has often been restricted by the rather static picture of protein-ligand complexes presented by crystal structures, despite the widely accepted importance of protein flexibility in biomolecular recognition. Here we report a detailed experimental and computational study of the drug target, human heat shock protein 90, to explore the contribution of protein dynamics to the binding thermodynamics and kinetics of drug-like compounds. We observe that their binding properties depend on whether the protein has a loop or a helical conformation in the binding site of the ligand-bound state. Compounds bound to the helical conformation display slow association and dissociation rates, high-affinity and high cellular efficacy, and predominantly entropically driven binding. An important entropic contribution comes from the greater flexibility of the helical relative to the loop conformation in the ligand-bound state. This unusual mechanism suggests increasing target flexibility in the bound state by ligand design as a new strategy for drug discovery.
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    Ferina, J.; Daggett, V. Visualizing protein folding and unfolding. J. Mol. Biol. 2019, 431, 1540– 1564,  DOI: 10.1016/j.jmb.2019.02.026
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    Visualizing Protein Folding and Unfolding
    Ferina, Jennifer; Daggett, Valerie
    Journal of Molecular Biology (2019), 431 (8), 1540-1564CODEN: JMOBAK; ISSN:0022-2836. (Elsevier Ltd.)
    A review. Protein folding/unfolding is a complicated process that defies high-resoln. characterization by exptl. methods. As an alternative, atomistic mol. dynamics simulations are now routinely employed to elucidate and magnify the accompanying conformational changes and the role of solvent in the folding process. However, the level of detail necessary to map the process at high spatial-temporal resoln. provides an overwhelming amt. of data. As more and better tools are developed for anal. of these large data sets and validation of the simulations, one is still left with the problem of visualizing the results in ways that provide insight into the folding/unfolding process. While viewing and interrogating static crystal structures has become commonplace, more and different approaches are required for dynamic, interconverting, unfolding, and refolding proteins. Here the authors review a variety of approaches, ranging from straightforward to complex and unintuitive for multiscale anal. and visualization of protein folding and unfolding.
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    Zambrano, R.; Jamroz, M.; Szczasiuk, A.; Pujols, J.; Kmiecik, S.; Ventura, S. AGGRESCAN3D (A3D): server for prediction of aggregation properties of protein structures. Nucleic Acids Res. 2015, 43, W306– 313,  DOI: 10.1093/nar/gkv359
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    AGGRESCAN3D (A3D): server for prediction of aggregation properties of protein structures
    Zambrano, Rafael; Jamroz, Michal; Szczasiuk, Agata; Pujols, Jordi; Kmiecik, Sebastian; Ventura, Salvador
    Nucleic Acids Research (2015), 43 (W1), W306-W313CODEN: NARHAD; ISSN:0305-1048. (Oxford University Press)
    Protein aggregation underlies an increasing no. of disorders and constitutes a major bottleneck in the development of therapeutic proteins. Our present understanding on the mol. determinants of protein aggregation has crystd. in a series of predictive algorithms to identify aggregation-prone sites. A majority of these methods rely only on sequence. Therefore, they find difficulties to predict the aggregation properties of folded globular proteins, where aggregation-prone sites are often not contiguous in sequence or buried inside the native structure. The AGGRESCAN3D (A3D) server overcomes these limitations by taking into account the protein structure and the exptl. aggregation propensity scale from the well-established AGGRESCAN method. Using the A3D server, the identified aggregation-prone residues can be virtually mutated to design variants with increased soly., or to test the impact of pathogenic mutations. Addnl., A3D server enables to take into account the dynamic fluctuations of protein structure in soln., which may influence aggregation propensity. This is possible in A3D Dynamic Mode that exploits the CABS-flex approach for the fast simulations of flexibility of globular proteins.
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    Goel, B.; Bhardwaj, N.; Tripathi, N.; Jain, S. K. Drug discovery of small molecules for the treatment of COVID-19: a review on clinical studies. Mini-Rev. Med. Chem. 2021, 21, 1431,  DOI: 10.2174/1389557521666201228145755
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    Drug Discovery of Small Molecules for the Treatment of COVID-19: A Review on Clinical Studies
    Goel, Bharat; Bhardwaj, Nivedita; Tripathi, Nancy; Jain, Shreyans K.
    Mini-Reviews in Medicinal Chemistry (2021), 21 (12), 1431-1456CODEN: MMCIAE; ISSN:1389-5575. (Bentham Science Publishers Ltd.)
    A review. Recently, a sudden outbreak of novel coronavirus disease (COVID-19) was caused by a zoonotic virus known as severe acute respiratory syndrome coronavirus (SARS-CoV-2). It has caused pandemic situations around the globe affecting the lives of millions of people. So far, no drug has been approved for the treatment of SARS-CoV-2 infected patients. As of now, more than 1000 clin. trials are going on for repurposing of FDA-approved drugs and for evaluating the safety and efficiency of exptl. antiviral mols. to combat COVID-19. Since the development of new drugs may require months to years to reach the market, this review focusses on the potential of existing small mol. FDA approved drugs and the mols. already in the clin. pipeline against viral infections like HIV, hepatitis B, Ebola virus, and other viruses of coronavirus family (SARS-CoV and MERS-CoV). The review also discusses the natural products and traditional medicines in clin. studies against COVID-19. Currently, 1978 studies are active, 143 completed and 4 posted results (as of June 13, 2020) on clinicaltrials.gov.
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    Pant, S.; Singh, M.; Ravichandiran, V.; Murty, U. S. N.; Srivastava, H. K. Peptide-like and small-molecule inhibitors against COVID-19. J. Biomol. Struct. Dyn. 2021, 39, 2904,  DOI: 10.1080/07391102.2020.1757510
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    Peptide-like and small-molecule inhibitors against Covid-19
    Pant, Suyash; Singh, Meenakshi; Ravichandiran, V.; Murty, U. S. N.; Srivastava, Hemant Kumar
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    Coronavirus disease strain (SARS-CoV-2) was discovered in 2019, and it is spreading very fast around the world causing the disease Covid-19. Currently, >1.6 million individuals are infected, and several thousand are dead across the globe because of Covid-19. We utilized the in-silico approaches to identify possible protease inhibitors against SARS-CoV-2. Potential compds. were screened from the CHEMBL database, ZINC database, FDA approved drugs, and mols. under clin. trials. Our study is based on 6Y2F and 6W63 co-crystd. structures available in the protein data bank (PDB). Seven hundred compds. from ZINC/CHEMBL databases and 1400 compds. from drug-bank were selected based on pos. interactions with the reported binding site. All the selected compds. were subjected to std.-precision (SP) and extra-precision (XP) mode of docking. Generated docked poses were carefully visualized for known interactions within the binding site. Mol. mechanics-generalized born surface area (MM-GBSA) calcns. were performed to screen the best compds. based on docking scores and binding energy values. Mol. dynamics (MD) simulations were carried out on 4 selected compds. from the CHEMBL database to validate the stability and interactions. MD simulations were also performed on the PDB structure 6YF2F to understand the differences between screened mols. and co-crystd. ligand. We screened 300 potential compds. from various databases, and 66 potential compds. from FDA approved drugs. Cobicistat, ritonavir, lopinavir, and darunavir are in the top screened mols. from FDA approved drugs. The screened drugs and mols. may be helpful in fighting with SARS-CoV-2 after further studies.
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  23. Salman Ali Khan, Alamgir Khan, Komal Zia, Ihab Shawish, Assem Barakat, Zaheer Ul-Haq. Cheminformatics-Based Discovery of Potential Chemical Probe Inhibitors of Omicron Spike Protein. International Journal of Molecular Sciences 2022, 23 (18) , 10315. https://doi.org/10.3390/ijms231810315
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  26. Akshay Chenna, Wajihul H Khan, Rozaleen Dash, Anurag S Rathore, Gaurav Goel. Template-based design of peptides to inhibit SARS-CoV-2 RNA-dependent RNA polymerase complexation. 2022https://doi.org/10.1101/2022.01.24.477502
  27. Ying-Chiang J. Lee, Jaden D. Shirkey, Jongbeom Park, Karishma Bisht, Alexis J. Cowan. An Overview of Antiviral Peptides and Rational Biodesign Considerations. BioDesign Research 2022, 2022 , 9898241. https://doi.org/10.34133/2022/9898241
  28. Narcis Fernandez-Fuentes, Ruben Molina, Baldo Oliva. A Collection of Designed Peptides to Target SARS-CoV-2 Spike RBD—ACE2 Interaction. International Journal of Molecular Sciences 2021, 22 (21) , 11627. https://doi.org/10.3390/ijms222111627
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  • Abstract

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    Figure 1

    Figure 1. Interaction of ACE2 with S-RBD. (a) Surface representation of the complex between the receptor binding (S-RBD) domain of SARS-CoV-2 Spike protein (yellow) and the human ACE2 receptor (pink) (PDB ID: 6M0J). The portion of the ACE2 domain including main interacting residues of helices α1 (I21, Q24, T27, F28, D30, K31, H34, E35, E37, D38, Y41, Q42), α2 (L79, M82, Y83), and α3 (N330, K419, D430, E431) and β sheets β3 and β4 (K353, G354, D355, and R357) are drawn in green. (b) A closer view displays the interacting residues at the interface site. Figure created by PyMol (Molecular Graphics System, ver. 1.2r3pre, Schrödinger, LLC).

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    Figure 2

    Figure 2. Stick representation of residues involved in the interprotomer interaction of S-RBD. (a) Side view of the surface representation of the interactions within ACE2 and S-RRBD (PDB ID: 6M0J). (b) Residues involved in the subunit interaction are shown in green (cartoon transparency is set to 40%). Four contact regions are located in the α1, α2and α3 helices and in β3 and β4 of ACE2 and S-RBD. Figure created by PyMol (Molecular Graphics System, ver. 1.2r3pre, Schrödinger, LLC).

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    Figure 3

    Figure 3. (a) Heat maps representing the pairwise backbone RMSD matrix of SARS-CoV-2 S-RBD protein calculated for the backbone along 50 ns of MD simulation from systems including peptides with stable binding to S-RBD. The unliganded protein (apo-RBD) is included for comparison. The simulation corresponding to apo-RBD displays a higher RMSD in comparison with the matrices originated for peptides 1, 2, 5, and 6. Indicating a less flexible conformation of S-RBD. (b) The unliganded protein (ACE2:S-RBD) is included for comparison

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    Figure 4

    Figure 4. α-Carbon RMSF analysis for the peptide-S-RBD systems. (a) α-Carbon RMSF profiles of all studied peptides, apo-S-RBD, and ACE2 are presented for comparison. (b) RMSF structural representation of apo-S-RBD and ACE2:S-RBD. (c) structural representation of peptide:S-RBD complexes including the binding of the peptides across 10 representative snapshots. Normalized scale for peptides 1–5; peptide 6 is presented with its own scale.

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    Figure 5

    Figure 5. (a) Binding analysis for the interaction between S-RBD and ACE2. (a) Luciferase-based assay. 293T cells were transfected with the ACE2 or S-RBD expression constructs. 48 h post-transfection, and luciferase assays were performed on 20 μg total protein from cell lysates using FMZ as a substrate (n = 3, mean ± SD; one-way ANOVA, ***p < 0.005 relative to smBiT-ACE2 alone, Dunnett’s correction for multiple comparisons). (b) MST analysis of peptide 1–6 binding to recombinant S-RBD. The concentration of S-RBD is kept constant at 50 nM, while the ligand concentration varies from 12.5 μM to 0.19 nM. Serial titrations result in measurable changes in the fluorescence signal within a temperature gradient that can be used to calculate the dissociation constant (Kd). The curve is shown as ΔFnorm (change of Fnorm with respect to the zero-ligand concentration) against S-RBD concentration on a log scale.

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      Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved α-ketoamide inhibitors
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      >> More from SciFinder ®
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      Structure of Mpro from SARS-CoV-2 and discovery of its inhibitors
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      Abstr.: A new coronavirus, known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is the etiol. agent responsible for the 2019-2020 viral pneumonia outbreak of coronavirus disease 2019 (COVID-19). Currently, there are no targeted therapeutic agents for the treatment of this disease, and effective treatment options remain very limited. Here, we describe the results of a program that aimed to rapidly discover lead compds. for clin. use, by combining structure-assisted drug design, virtual drug screening and high-throughput screening. This program focused on identifying drug leads that target main protease (Mpro) of SARS-CoV-2: Mpro is a key enzyme of coronaviruses and has a pivotal role in mediating viral replication and transcription, making it an attractive drug target for SARS-CoV-2. We identified a mechanism-based inhibitor (N3) by computer-aided drug design, and then detd. the crystal structure of Mpro of SARS-CoV-2 in complex with this compd. Through a combination of structure-based virtual and high-throughput screening, we assayed more than 10,000 compds.-including approved drugs, drug candidates in clin. trials and other pharmacol. active compds.-as inhibitors of Mpro. Six of these compds. inhibited Mpro, showing half-maximal inhibitory concn. values that ranged from 0.67 to 21.4μM. One of these compds. (ebselen) also exhibited promising antiviral activity in cell-based assays. Our results demonstrate the efficacy of our screening strategy, which can lead to the rapid discovery of drug leads with clin. potential in response to new infectious diseases for which no specific drugs or vaccines are available.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhtVyhsrrO&md5=b84f350fe9ce1109485df6caf814ba82
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhtlOhurzJ&md5=a8d06ec5240ed4d5224dfb3be7c76635
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      Identification of SARS-CoV-2 cell entry inhibitors by drug repurposing using in silico structure-based virtual screening approach
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      The rapidly spreading, highly contagious and pathogenic SARS-coronavirus 2 (SARS-CoV-2) assocd. Coronavirus Disease 2019 (COVID-19) has been declared as a pandemic by the World Health Organization (WHO). The novel 2019 SARS-CoV-2 enters the host cell by binding of the viral surface spike glycoprotein (S-protein) to cellular angiotensin converting enzyme 2 (ACE2) receptor. The virus specific mol. interaction with the host cell represents a promising therapeutic target for identifying SARS-CoV-2 antiviral drugs. The repurposing of drugs can provide a rapid and potential cure toward exponentially expanding COVID-19. Thereto, high throughput virtual screening approach was used to investigate FDA approved LOPAC library drugs against both the receptor binding domain of spike protein (S-RBD) and ACE2 host cell receptor. Primary screening identified a few promising mols. for both the targets, which were further analyzed in details by their binding energy, binding modes through mol. docking, dynamics and simulations. Evidently, GR 127935 hydrochloride hydrate, GNF-5, RS504393, TNP, and eptifibatide acetate were found binding to virus binding motifs of ACE2 receptor. Addnl., KT203, BMS195614, KT185, RS504393, and GSK1838705A were identified to bind at the receptor binding site on the viral S-protein. These identified mols. may effectively assist in controlling the rapid spread of SARS-CoV-2 by not only potentially inhibiting the virus at entry step but are also hypothesized to act as anti-inflammatory agents, which could impart relief in lung inflammation. Timely identification and detn. of an effective drug to combat and tranquilize the COVID-19 global crisis is the utmost need of hour. Further, prompt in vivo testing to validate the anti-SARS-CoV-2 inhibition efficiency by these mols. could save lives is justified.
      >> More from SciFinder ®
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      Drug discovery strategies for SARS-CoV-2
      Shyr, Zeenat A.; Gorshkov, Kirill; Chen, Catherine Z.; Zheng, Wei
      Journal of Pharmacology and Experimental Therapeutics (2020), 375 (1), 127-138CODEN: JPETAB; ISSN:1521-0103. (American Society for Pharmacology and Experimental Therapeutics)
      A review. Coronavirus disease 2019 (COVID-19) is a novel disease caused by the severe acute respiratory syndrome coronavirus (SARS-CoV)-2 virus that was first detected in Dec. of 2019 in Wuhan, China, and has rapidly spread worldwide. The search for a suitable vaccine as well as effective therapeutics for the treatment of COVID-19 is underway. Drug repurposing screens provide a useful and effective soln. for identifying potential therapeutics against SARS-CoV-2. For example, the exptl. drug remdesivir, originally developed for Ebola virus infections, has been approved by the US Food and Drug Administration as an emergency use treatment of COVID-19. However, the efficacy and toxicity of this drug need further improvements. In this review, we discuss recent findings on the pathol. of coronaviruses and the drug targets for the treatment of COVID-19. Both SARS-CoV-2-specific inhibitors and broad-spectrum anticoronavirus drugs against SARS-CoV, Middle East respiratory syndrome coronavirus, and SARS-CoV-2 will be valuable addns. to the anti-SARS-CoV-2 armament. A multitarget treatment approach with synergistic drug combinations contg. different mechanisms of action may be a practical therapeutic strategy for the treatment of severe COVID-19.
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    10. 10
      Gil, C.; Ginex, T.; Maestro, I.; Nozal, V.; Barrado-Gil, L.; Cuesta-Geijo, M.Á.; Urquiza, J.; Ramírez, D.; Alonso, C.; Campillo, N. E.; Martinez, A. COVID-19: drug targets and potential treatments. J. Med. Chem. 2020, 63, 12359– 12386,  DOI: 10.1021/acs.jmedchem.0c00606
      10
      COVID-19: Drug Targets and Potential Treatments
      Gil, Carmen; Ginex, Tiziana; Maestro, Ines; Nozal, Vanesa; Barrado-Gil, Lucia; Cuesta-Geijo, Miguel Angel; Urquiza, Jesus; Ramirez, David; Alonso, Covadonga; Campillo, Nuria E.; Martinez, Ana
      Journal of Medicinal Chemistry (2020), 63 (21), 12359-12386CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
      A review. Currently, the authors are immersed in a pandemic caused by the emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which severely threatens public health worldwide. Until now, no drug or vaccine has been approved to treat the severe disease caused by this coronavirus, COVID-19. The authors will focus on the main virus-based and host-based targets that can guide medicinal chem. efforts to discover new drugs for this devastating disease. In principle, all CoVs enzymes and proteins involved in viral replication and the control of host cellular machineries are potentially druggable targets in the search for therapeutic options for SARS-CoV-2. This perspective provides an overview of the main targets from a structural point of view, together with reported therapeutic compds. with activity against SARS-CoV-2 and/or other CoVs. Also, the role of innate immune response to coronavirus infection and the related therapeutic options will be presented.
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      11
      Immune response in COVID-19: addressing a pharmacological challenge by targeting pathways triggered by SARS-CoV-2
      Catanzaro Michele; Fagiani Francesca; Racchi Marco; Govoni Stefano; Lanni Cristina; Fagiani Francesca; Corsini Emanuela
      Signal transduction and targeted therapy (2020), 5 (1), 84 ISSN:.
      To date, no vaccines or effective drugs have been approved to prevent or treat COVID-19 and the current standard care relies on supportive treatments. Therefore, based on the fast and global spread of the virus, urgent investigations are warranted in order to develop preventive and therapeutic drugs. In this regard, treatments addressing the immunopathology of SARS-CoV-2 infection have become a major focus. Notably, while a rapid and well-coordinated immune response represents the first line of defense against viral infection, excessive inflammatory innate response and impaired adaptive host immune defense may lead to tissue damage both at the site of virus entry and at systemic level. Several studies highlight relevant changes occurring both in innate and adaptive immune system in COVID-19 patients. In particular, the massive cytokine and chemokine release, the so-called "cytokine storm", clearly reflects a widespread uncontrolled dysregulation of the host immune defense. Although the prospective of counteracting cytokine storm is compelling, a major limitation relies on the limited understanding of the immune signaling pathways triggered by SARS-CoV-2 infection. The identification of signaling pathways altered during viral infections may help to unravel the most relevant molecular cascades implicated in biological processes mediating viral infections and to unveil key molecular players that may be targeted. Thus, given the key role of the immune system in COVID-19, a deeper understanding of the mechanism behind the immune dysregulation might give us clues for the clinical management of the severe cases and for preventing the transition from mild to severe stages.
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      Wu, C.; Liu, Y.; Yang, Y.; Zhang, P.; Zhong, W.; Wang, Y.; Wang, Q.; Xu, Y.; Li, M.; Li, X.; Zheng, M.; Chen, L.; Li, H. Analysis of therapeutic targets for SARS-CoV-2 and discovery of potential drugs by computational methods. Acta Pharm. Sin. B 2020, 10, 766– 788,  DOI: 10.1016/j.apsb.2020.02.008
      12
      Analysis of therapeutic targets for SARS-CoV-2 and discovery of potential drugs by computational methods
      Wu, Canrong; Liu, Yang; Yang, Yueying; Zhang, Peng; Zhong, Wu; Wang, Yali; Wang, Qiqi; Xu, Yang; Li, Mingxue; Li, Xingzhou; Zheng, Mengzhu; Chen, Lixia; Li, Hua
      Acta Pharmaceutica Sinica B (2020), 10 (5), 766-788CODEN: APSBCW; ISSN:2211-3835. (Elsevier B.V.)
      SARS-CoV-2 has caused tens of thousands of infections and more than one thousand deaths. There are currently no registered therapies for treating coronavirus infections. Because of time consuming process of new drug development, drug repositioning may be the only soln. to the epidemic of sudden infectious diseases. We systematically analyzed all the proteins encoded by SARS-CoV-2 genes, compared them with proteins from other coronaviruses, predicted their structures, and built 19 structures that could be done by homol. modeling. By performing target-based virtual ligand screening, a total of 21 targets (including two human targets) were screened against compd. libraries including ZINC drug database and our own database of natural products. Structure and screening results of important targets such as 3-chymotrypsin-like protease (3CLpro), Spike, RNA-dependent RNA polymerase (RdRp), and papain like protease (PLpro) were discussed in detail. In addn., a database of 78 commonly used anti-viral drugs including those currently on the market and undergoing clin. trials for SARS-CoV-2 was constructed. Possible targets of these compds. and potential drugs acting on a certain target were predicted. This study will provide new lead compds. and targets for further in vitro and in vivo studies of SARS-CoV-2, new insights for those drugs currently ongoing clin. studies, and also possible new strategies for drug repositioning to treat SARS-CoV-2 infections.
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      VanPatten, S.; He, M.; Altiti, A.; F Cheng, K.; Ghanem, M. H.; Al-Abed, Y. Evidence supporting the use of peptides and peptidomimetics as potential SARS-CoV-2 (COVID-19) therapeutics. Future Med. Chem. 2020, 12, 1647– 1656,  DOI: 10.4155/fmc-2020-0180
      13
      Evidence supporting the use of peptides and peptidomimetics as potential SARS-CoV-2 (COVID-19) therapeutics
      VanPatten, Sonya; He, Mingzhu; Altiti, Ahmad; F Cheng, Kai; Ghanem, Mustafa H.; Al-Abed, Yousef
      Future Medicinal Chemistry (2020), 12 (18), 1647-1656CODEN: FMCUA7; ISSN:1756-8919. (Newlands Press Ltd.)
      A review. During a disease outbreak/pandemic situation such as COVID-19, researchers are in a prime position to identify and develop peptide-based therapies, which could be more rapidly and cost-effectively advanced into a clin. setting. One drawback of natural peptide drugs, however, is their proteolytic instability; peptidomimetics can help to overcome this caveat. In this review, we summarize peptide and peptide-based therapeutics that target one main entry pathway of SARS-CoV-2, which involves the host ACE2 receptor and viral spike (S) protein interaction. Furthermore, we discuss the advantages of peptidomimetics and other potential targets that have been studied using peptide-based therapeutics for COVID-19.
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      15
      mRNA display: from basic principles to macrocycle drug discovery
      Josephson, Kristopher; Ricardo, Alonso; Szostak, Jack W.
      Drug Discovery Today (2014), 19 (4), 388-399CODEN: DDTOFS; ISSN:1359-6446. (Elsevier Ltd.)
      A review. We describe a new discovery technol. that uses mRNA-display to rapidly synthesize and screen macrocyclic peptide libraries to explore a valuable region of chem. space typified by natural products. This technol. allows high-affinity peptidic macrocycles contg. modified backbones and unnatural side chains to be readily selected based on target binding. Success stories covering the first examples of these libraries suggest that they could be used for the discovery of intracellular protein-protein interaction inhibitors, highly selective enzyme inhibitors or synthetic replacements for monoclonal antibodies. The review concludes with a look to the future regarding how this technol. might be improved with respect to library design for cell permeability and bioavailability.
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    16. 16
      WHO. Draft landscape of COVID-19 candidate vaccines. https://www.who.int/news-room/q-a-detail/coronavirus-disease-(covid-19)-vaccines (accessed January 2021).
      There is no corresponding record for this reference.
    17. 17
      Voysey, M.; Clemens; Madhi, S.; Weckx, L. Y.; Folegatti, P. M. Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK. Lancet 2021, 397, 99– 111,  DOI: 10.1016/S0140-6736(20)32661-1
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      Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomized controlled trials in Brazil, South Africa, and the UK
      Voysey, Merryn; Clemens, Sue Ann Costa; Madhi, Shabir A.; Weckx, Lily Y.; Folegatti, Pedro M.; Aley, Parvinder K.; Angus, Brian; Baillie, Vicky L.; Barnabas, Shaun L.; Bhorat, Qasim E.; Bibi, Sagida; Briner, Carmen; Cicconi, Paola; Collins, Andrea M.; Colin-Jones, Rachel; Cutland, Clare L.; Darton, Thomas C.; Dheda, Keertan; Duncan, Christopher J. A.; Emary, Katherine R. W.; Ewer, Katie J.; Fairlie, Lee; Faust, Saul N.; Feng, Shuo; Ferreira, Daniela M.; Finn, Adam; Goodman, Anna L.; Green, Catherine M.; Green, Christopher A.; Heath, Paul T.; Hill, Catherine; Hill, Helen; Hirsch, Ian; Hodgson, Susanne H. C.; Izu, Alane; Jackson, Susan; Jenkin, Daniel; Joe, Carina C. D.; Kerridge, Simon; Koen, Anthonet; Kwatra, Gaurav; Lazarus, Rajeka; Lawrie, Alison M.; Lelliott, Alice; Libri, Vincenzo; Lillie, Patrick J.; Mallory, Raburn; Mendes, Ana V. A.; Milan, Eveline P.; Minassian, Angela M.; McGregor, Alastair; Morrison, Hazel; Mujadidi, Yama F.; Nana, Anusha; O'Reilly, Peter J.; Padayachee, Sherman D.; Pittella, Ana; Plested, Emma; Pollock, Katrina M.; Ramasamy, Maheshi N.; Rhead, Sarah; Schwarzbold, Alexandre V.; Singh, Nisha; Smith, Andrew; Song, Rinn; Snape, Matthew D.; Sprinz, Eduardo; Sutherland, Rebecca K.; Tarrant, Richard; Thomson, Emma C.; Torok, M. Estee; Toshner, Mark; Turner, David P. J.; Vekemans, Johan; Villafana, Tonya L.; Watson, Marion E. E.; Williams, Christopher J.; Douglas, Alexander D.; Hill, Adrian V. S.; Lambe, Teresa; Gilbert, Sarah C.; Pollard, Andrew J.
      Lancet (2021), 397 (10269), 99-111CODEN: LANCAO; ISSN:0140-6736. (Elsevier Ltd.)
      A safe and efficacious vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), if deployed with high coverage, could contribute to the control of the COVID-19 pandemic. We evaluated the safety and efficacy of the ChAdOx1 nCoV-19 vaccine in a pooled interim anal. of four trials. This anal. includes data from four ongoing blinded, randomized, controlled trials done across the UK, Brazil, and South Africa. Participants aged 18 years and older were randomly assigned (1:1) to ChAdOx1 nCoV-19 vaccine or control (meningococcal group A, C, W, and Y conjugate vaccine or saline). Participants in the ChAdOx1 nCoV-19 group received two doses contg. 5 x 1010 viral particles (std. dose; SD/SD cohort); a subset in the UK trial received a half dose as their first dose (low dose) and a std. dose as their second dose (LD/SD cohort). The primary efficacy anal. included symptomatic COVID-19 in seroneg. participants with a nucleic acid amplification test-pos. swab more than 14 days after a second dose of vaccine. Participants were analyzed according to treatment received, with data cutoff on Nov 4, 2020. Vaccine efficacy was calcd. as 1 - relative risk derived from a robust Poisson regression model adjusted for age. Studies are registered at ISRCTN89951424 and ClinicalTrials.gov, NCT04324606, NCT04400838, and NCT04444674. Between Apr. 23 and Nov 4, 2020, 23,848 participants were enrolled and 11,636 participants (7548 in the UK, 4088 in Brazil) were included in the interim primary efficacy anal. In participants who received two std. doses, vaccine efficacy was 62.1% (95% CI 41.0-75.7; 27 [0.6%] of 4440 in the ChAdOx1 nCoV-19 group vs. 71 [1.6%] of 4455 in the control group) and in participants who received a low dose followed by a std. dose, efficacy was 90.0% (67.4-97.0; three [0.2%] of 1367 vs 30 [2.2%] of 1374; pinteraction=0.010). Overall vaccine efficacy across both groups was 70.4% (95.8% CI 54.8-80.6; 30 [0.5%] of 5807 vs 101 [1.7%] of 5829). From 21 days after the first dose, there were ten cases hospitalized for COVID-19, all in the control arm; two were classified as severe COVID-19, including one death. There were 74,341 person-months of safety follow-up (median 3.4 mo, IQR 1.3-4.8): 175 severe adverse events occurred in 168 participants, 84 events in the ChAdOx1 nCoV-19 group and 91 in the control group. Three events were classified as possibly related to a vaccine: one in the ChAdOx1 nCoV-19 group, one in the control group, and one in a participant who remains masked to group allocation. ChAdOx1 nCoV-19 has an acceptable safety profile and has been found to be efficacious against symptomatic COVID-19 in this interim anal. of ongoing clin. trials.
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    18. 18
      Polack, F. P.; Thomas, S. J.; Kitchin, N. Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine. N. Engl. J. Med. 2020, 383, 2603– 2615,  DOI: 10.1056/NEJMoa2034577
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      Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine
      Polack, Fernando P.; Thomas, Stephen J.; Kitchin, Nicholas; Absalon, Judith; Gurtman, Alejandra; Lockhart, Stephen; Perez, John L.; Marc, Gonzalo Perez; Moreira, Edson D.; Zerbini, Cristiano; Bailey, Ruth; Swanson, Kena A.; Roychoudhury, Satrajit; Koury, Kenneth; Li, Ping; Kalina, Warren V.; Cooper, David; Frenck, Robert W., Jr.; Hammitt, Laura L.; Tureci, Ozlem; Nell, Haylene; Schaefer, Axel; Unal, Serhat; Tresnan, Dina B.; Mather, Susan; Dormitzer, Philip R.; Sahin, Ugur; Jansen, Kathrin U.; Gruber, William C.
      New England Journal of Medicine (2020), 383 (27), 2603-2615CODEN: NEJMAG; ISSN:1533-4406. (Massachusetts Medical Society)
      A review. Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the resulting coronavirus disease 2019 (Covid-19) have afflicted tens of millions of people in a worldwide pandemic. Safe and effective vaccines are needed urgently. methods In an ongoing multinational, placebo-controlled, observer-blinded, pivotal efficacy trial, we randomly assigned persons 16 years of age or older in a 1:1 ratio to receive two doses, 21 days apart, of either placebo or the BNT162b2 vaccine candidate (30μg per dose). BNT162b2 is a lipid nanoparticle-formulated, nucleoside-modified RNA vaccine that encodes a prefusion stabilized, membrane-anchored SARS-CoV-2 full-length spike protein. The primary end points were efficacy of the vaccine against lab.-confirmed Covid-19 and safety. results A total of 43,548 participants underwent randomization, of whom 43,448 received injections: 21,720 with BNT162b2 and 21,728 with placebo. There were 8 cases of Covid-19 with onset at least 7 days after the second dose among participants assigned to receive BNT162b2 and 162 cases among those assigned to placebo; BNT162b2 was 95% effective in preventing Covid-19 (95% credible interval, 90.3 to 97.6). Similar vaccine efficacy (generally 90 to 100%) was obsd. across subgroups defined by age, sex, race, ethnicity, baseline body-mass index, and the presence of coexisting conditions. Among 10 cases of severe Covid-19 with onset after the first dose, 9 occurred in placebo recipients and 1 in a BNT162b2 recipient. The safety profile of BNT162b2 was characterized by short-term, mild-to-moderate pain at the injection site, fatigue, and headache. The incidence of serious adverse events was low and was similar in the vaccine and placebo groups. conclusions A two-dose regimen of BNT162b2 conferred 95% protection against Covid-19 in persons 16 years of age or older. Safety over a median of 2 mo was similar to that of other viral vaccines.
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    19. 19
      Baden, L. R.; El Sahly, H. M.; Essink, B. Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine. N. Engl. J. Med. 2021, 384, 403– 416,  DOI: 10.1056/NEJMoa2035389
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      Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine
      Baden, L. R.; El Sahly, H. M.; Essink, B.; Kotloff, K.; Frey, S.; Novak, R.; Diemert, D.; Spector, S. A.; Rouphael, N.; Creech, C. B.; McGettigan, J.; Khetan, S.; Segall, N.; Solis, J.; Brosz, A.; Fierro, C.; Schwartz, H.; Neuzil, K.; Corey, L.; Gilbert, P.; Janes, H.; Follmann, D.; Marovich, M.; Mascola, J.; Polakowski, L.; Ledgerwood, J.; Graham, B. S.; Bennett, H.; Pajon, R.; Knightly, C.; Leav, B.; Deng, W.; Zhou, H.; Han, S.; Ivarsson, M.; Miller, J.; Zaks, T.
      New England Journal of Medicine (2021), 384 (5), 403-416CODEN: NEJMAG; ISSN:1533-4406. (Massachusetts Medical Society)
      Vaccines are needed to prevent coronavirus disease 2019 (Covid-19) and to protect persons who are at high risk for complications. The mRNA-1273 vaccine is a lipid nanoparticle-encapsulated mRNA-based vaccine that encodes the prefusion stabilized full-length spike protein of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes Covid-19. This phase 3 randomized, observer-blinded, placebo-controlled trial was conducted at 99 centers across the United States. Persons at high risk for SARS-CoV-2 infection or its complications were randomly assigned in a 1:1 ratio to receive two i.m. injections of mRNA-1273 (100μg) or placebo 28 days apart. The primary end point was prevention of Covid-19 illness with onset at least 14 days after the second injection in participants who had not previously been infected with SARS-CoV-2. The trial enrolled 30,420 volunteers who were randomly assigned in a 1:1 ratio to receive either vaccine or placebo (15,210 participants in each group). More than 96% of participants received both injections, and 2.2% had evidence (serol., virol., or both) of SARS-CoV-2 infection at baseline. Symptomatic Covid-19 illness was confirmed in 185 participants in the placebo group (56.5 per 1000 person-years; 95% confidence interval [CI], 48.7 to 65.3) and in 11 participants in the mRNA-1273 group (3.3 per 1000 person-years; 95% CI, 1.7 to 6.0); vaccine efficacy was 94.1% (95% CI, 89.3 to 96.8%; P<0.001). Efficacy was similar across key secondary analyses, including assessment 14 days after the first dose, analyses that included participants who had evidence of SARS-CoV-2 infection at baseline, and analyses in participants 65 years of age or older. Severe Covid-19 occurred in 30 participants, with one fatality; all 30 were in the placebo group. Moderate, transient reactogenicity after vaccination occurred more frequently in the mRNA-1273 group. Serious adverse events were rare, and the incidence was similar in the two groups. The mRNA-1273 vaccine showed 94.1% efficacy at preventing Covid-19 illness, including severe disease. Aside from transient local and systemic reactions, no safety concerns were identified.
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    20. 20
      Kovyrshina, A. V.; Dolzhikova, I. V.; Grousova, D. M. A heterologous virus-vectored vaccine for prevention of middle east respiratory syndrome induces long protective immune response against MERS-CoV. Immunologiya 2020, 41, 135– 43,  DOI: 10.33029/0206-4952-2020-41-2-135-143
      There is no corresponding record for this reference.
    21. 21
      Logunov, D. Y.; Dolzhikova, I. V.; Zubkova, O. V. Safety and immunogenicity of an rAd26 and rAd5 vector-based heterologous prime-boost COVID-19 vaccine in two formulations: two open, non-randomised phase 1/2 studies from Russia. Lancet 2020, 396, 887– 97,  DOI: 10.1016/S0140-6736(20)31866-3
      21
      Safety and immunogenicity of an rAd26 and rAd5 vector-based heterologous prime-boost COVID-19 vaccine in two formulations: two open, non-randomised phase 1/2 studies from Russia
      Logunov, Denis Y.; Dolzhikova, Inna V.; Zubkova, Olga V.; Tukhvatullin, Amir I.; Shcheblyakov, Dmitry V.; Dzharullaeva, Alina S.; Grousova, Daria M.; Erokhova, Alina S.; Kovyrshina, Anna V.; Botikov, Andrei G.; Izhaeva, Fatima M.; Popova, Olga; Ozharovskaya, Tatiana A.; Esmagambetov, Ilias B.; Favorskaya, Irina A.; Zrelkin, Denis I.; Voronina, Daria V.; Shcherbinin, Dmitry N.; Semikhin, Alexander S.; Simakova, Yana V.; Tokarskaya, Elizaveta A.; Lubenets, Nadezhda L.; Egorova, Daria A.; Shmarov, Maksim M.; Nikitenko, Natalia A.; Morozova, Lola F.; Smolyarchuk, Elena A.; Kryukov, Evgeny V.; Babira, Vladimir F.; Borisevich, Sergei V.; Naroditsky, Boris S.; Gintsburg, Alexander L.
      Lancet (2020), 396 (10255), 887-897CODEN: LANCAO; ISSN:0140-6736. (Elsevier Ltd.)
      We developed a heterologous COVID-19 vaccine consisting of 2 components, a recombinant adenovirus type 26 (rAd26) vector and a recombinant adenovirus type 5 (rAd5) vector, both carrying the gene for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike glycoprotein (rAd26-S and rAd5-S). We aimed to assess the safety and immunogenicity of 2 formulations (frozen and lyophilized) of this vaccine. We did 2 open, non-randomized phase 1/2 studies at 2 hospitals in Russia. We enrolled healthy adult volunteers (men and women) aged 18-60 yr to both studies. In phase 1 of each study, we administered i.m. on day 0 either 1 dose of rAd26-S or 1 dose of rAd5-S and assessed the safety of the 2 components for 28 days. In phase 2 of the study, which began no earlier than 5 days after phase 1 vaccination, we administered i.m. a prime-boost vaccination, with rAd26-S given on day 0 and rAd5-S on day 21. Primary outcome measures were antigen-specific humoral immunity (SARS-CoV-2-specific antibodies measured by ELISA on days 0, 14, 21, 28, and 42) and safety (no. of participants with adverse events monitored throughout the study). Secondary outcome measures were antigen-specific cellular immunity (T-cell responses and interferon-γ concn.) and change in neutralizing antibodies (detected with a SARS-CoV-2 neutralization assay). These trials are registered with ClinicalTrials.gov, NCT04436471 and NCT04437875. Between June 18 and Aug 3, 2020, we enrolled 76 participants to the 2 studies (38 in each study). In each study, 9 volunteers received rAd26-S in phase 1, 9 received rAd5-S in phase 1, and 20 received rAd26-S and rAd5-S in phase 2. Both vaccine formulations were safe and well tolerated. The most common adverse events were pain at injection site (44 [58%]), hyperthermia (38 [50%]), headache (32 [42%]), asthenia (21 [28%]), and muscle and joint pain (18 [24%]). Most adverse events were mild and no serious adverse events were detected. All participants produced antibodies to SARS-CoV-2 glycoprotein. At day 42, receptor binding domain-specific IgG titers were 14 703 with the frozen formulation and 11,143 with the lyophilized formulation, and neutralizing antibodies were 49·25 with the frozen formulation and 45·95 with the lyophilized formulation, with a seroconversion rate of 100%. Cell-mediated responses were detected in all participants at day 28, with median cell proliferation of 2.5% CD4+ and 1.3% CD8+ with the frozen formulation, and a median cell proliferation of 1.3% CD4+ and 1.1% CD8+ with the lyophilized formulation. The heterologous rAd26 and rAd5 vector-based COVID-19 vaccine has a good safety profile and induced strong humoral and cellular immune responses in participants. Further investigation is needed of the effectiveness of this vaccine for prevention of COVID-19. Ministry of Health of the Russian Federation.
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    22. 22
      Logunov, D. Y.; Dolzhikova, I. V.; Shcheblyakov, D. V.; Tukhvatulin, A. Safety and efficacy of an rAd26 and rAd5 vector-based heterologous prime-boost COVID-19 vaccine: an interim analysis of a randomised controlled phase 3 trial in Russia. Lancet 2021, 397, 671,  DOI: 10.1016/S0140-6736(21)00234-8
      22
      Safety and efficacy of an rAd26 and rAd5 vector-based heterologous prime-boost COVID-19 vaccine: an interim analysis of a randomized controlled phase 3 trial in Russia
      Logunov, Denis Y.; Dolzhikova, Inna V.; Shcheblyakov, Dmitry V.; Tukhvatulin, Amir I.; Zubkova, Olga V.; Dzharullaeva, Alina S.; Kovyrshina, Anna V.; Lubenets, Nadezhda L.; Grousova, Daria M.; Erokhova, Alina S.; Botikov, Andrei G.; Izhaeva, Fatima M.; Popova, Olga; Ozharovskaya, Tatiana A.; Esmagambetov, Ilias B.; Favorskaya, Irina A.; Zrelkin, Denis I.; Voronina, Daria V.; Shcherbinin, Dmitry N.; Semikhin, Alexander S.; Simakova, Yana V.; Tokarskaya, Elizaveta A.; Egorova, Daria A.; Shmarov, Maksim M.; Nikitenko, Natalia A.; Gushchin, Vladimir A.; Smolyarchuk, Elena A.; Zyryanov, Sergey K.; Borisevich, Sergei V.; Naroditsky, Boris S.; Gintsburg, Alexander L.
      Lancet (2021), 397 (10275), 671-681CODEN: LANCAO; ISSN:0140-6736. (Elsevier Ltd.)
      A heterologous recombinant adenovirus (rAd)-based vaccine, Gam-COVID-Vac (Sputnik V), showed a good safety profile and induced strong humoral and cellular immune responses in participants in phase 1/2 clin. trials. Here, we report preliminary results on the efficacy and safety of Gam-COVID-Vac from the interim anal. of this phase 3 trial. We did a randomized, double-blind, placebo-controlled, phase 3 trial at 25 hospitals and polyclinics in Moscow, Russia. We included participants aged at least 18 years, with neg. SARS-CoV-2 PCR and IgG and IgM tests, no infectious diseases in the 14 days before enrollment, and no other vaccinations in the 30 days before enrollment. Participants were randomly assigned (3:1) to receive vaccine or placebo, with stratification by age group. Investigators, participants, and all study staff were masked to group assignment. The vaccine was administered (0·5 mL/dose) i.m. in a prime-boost regimen: a 21-day interval between the first dose (rAd26) and the second dose (rAd5), both vectors carrying the gene for the full-length SARS-CoV-2 glycoprotein S. The primary outcome was the proportion of participants with PCR-confirmed COVID-19 from day 21 after receiving the first dose. All analyses excluded participants with protocol violations: the primary outcome was assessed in participants who had received two doses of vaccine or placebo, serious adverse events were assessed in all participants who had received at least one dose at the time of database lock, and rare adverse events were assessed in all participants who had received two doses and for whom all available data were verified in the case report form at the time of database lock. The trial is registered at ClinicalTrials.gov (NCT04530396). Between Sept 7 and Nov 24, 2020, 21 977 adults were randomly assigned to the vaccine group (n=16 501) or the placebo group (n=5476). 19 866 received two doses of vaccine or placebo and were included in the primary outcome anal. From 21 days after the first dose of vaccine (the day of dose 2), 16 (0·1%) of 14 964 participants in the vaccine group and 62 (1·3%) of 4902 in the placebo group were confirmed to have COVID-19; vaccine efficacy was 91·6% (95% CI 85·6-95·2). Most reported adverse events were grade 1 (7485 [94·0%] of 7966 total events). 45 (0·3%) of 16 427 participants in the vaccine group and 23 (0·4%) of 5435 participants in the placebo group had serious adverse events; none were considered assocd. with vaccination, with confirmation from the independent data monitoring committee. Four deaths were reported during the study (three [<0·1%] of 16 427 participants in the vaccine group and one [<0·1%] of 5435 participants in the placebo group), none of which were considered related to the vaccine. This interim anal. of the phase 3 trial of Gam-COVID-Vac showed 91·6% efficacy against COVID-19 and was well tolerated in a large cohort. Moscow City Health Department, Russian Direct Investment Fund, Sberbank, and RUSAL.
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    23. 23
      WHO. Transmission of SARS-CoV-2: implications for infection prevention precautions. https://www.who.int/news-room/commentaries/detail/transmission-of-sars-cov-2-implications-for-infection-prevention-precautions (accessed January 2020).
      There is no corresponding record for this reference.
    24. 24
      Centers for disease control and prevention. Interim clinical guidance for management of patients with confirmed coronavirus disease (COVID-19). https://www.cdc.gov/coronavirus/2019-ncov/hcp/ (accessed May 2020).
      There is no corresponding record for this reference.
    25. 25
      WHO. Target product profiles for COVID-19 vaccines , 2020. https://www.who.int/publications/m/item/who-target-product-profiles-for-covid-19-vaccines (accessed January 2020).
      There is no corresponding record for this reference.
    26. 26
      Amanat, F. K. SARS-CoV-2 vaccines: status report. Immunity 2020, 52, 583,  DOI: 10.1016/j.immuni.2020.03.007
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      SARS-CoV-2 Vaccines: Status Report
      Amanat, Fatima; Krammer, Florian
      Immunity (2020), 52 (4), 583-589CODEN: IUNIEH; ISSN:1074-7613. (Elsevier Inc.)
      A review. SARS-CoV-2, the causal agent of COVID-19, first emerged in late 2019 in China. It has since infected more than 870,000 individuals and caused more than 43,000 deaths globally. Here, we discuss therapeutic and prophylactic interventions for SARS-CoV-2 with a focus on vaccine development and its challenges. Vaccines are being rapidly developed but will likely come too late to affect the first wave of a potential pandemic. Nevertheless, crit. lessons can be learned for the development of vaccines against rapidly emerging viruses. Importantly, SARS-CoV-2 vaccines will be essential to reducing morbidity and mortality if the virus establishes itself in the population.
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    27. 27
      Chen, W. H.; Strych, U.; Hotez, P. J.; Bottazzi, M. E. The SARS-CoV-2 vaccine pipeline: an overview. Curr. Trop Med. Rep. 2020, 7, 61,  DOI: 10.1007/s40475-020-00201-6
      27
      The SARS-CoV-2 Vaccine Pipeline: an Overview
      Chen Wen-Hsiang; Strych Ulrich; Hotez Peter J; Bottazzi Maria Elena
      Current tropical medicine reports (2020), 7 (2), 61-64 ISSN:2196-3045.
      Purpose of Review: The goal of this review is to provide a timely overview on efforts to develop a vaccine for the 2019 novel coronavirus SARS-CoV-2, the causative agent of coronavirus disease (COVID-19). Recent Findings: Previous research efforts to develop a severe acute respiratory syndrome coronavirus (SARS-CoV) vaccine in the years following the 2003 pandemic have opened the door for investigators to design vaccine concepts and approaches for the COVID-19 epidemic in China. Both SARS-CoV and SARS-CoV-2 exhibit a high degree of genetic similarity and bind to the same host cell ACE2 receptor. Based on previous experience with SARS-CoV vaccines, it is expected that all COVID-19 vaccines will require careful safety evaluations for immunopotentiation that could lead to increased infectivity or eosinophilic infiltration. Besides this, a COVID-19 vaccine target product profile must address vaccinating at-risk human populations including frontline healthcare workers, individuals over the age of 60, and those with underlying and debilitating chronic conditions. Among the vaccine technologies under evaluation are whole virus vaccines, recombinant protein subunit vaccines, and nucleic acid vaccines. Summary: Each current vaccine strategy has distinct advantages and disadvantages. Therefore, it is paramount that multiple strategies be advanced quickly and then evaluated for safety and efficacy. Ultimately, the safety studies to minimize undesired immunopotentiation will become the most significant bottleneck in terms of time.
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    28. 28
      Leader, B.; Baca, Q. J.; Golan, D. E. Protein therapeutics: a summary and pharmacological classification. Nat. Rev. Drug Discovery 2008, 7, 21– 39,  DOI: 10.1038/nrd2399
      28
      Protein therapeutics: a summary and pharmacological classification
      Leader, Benjamin; Baca, Quentin J.; Golan, David E.
      Nature Reviews Drug Discovery (2008), 7 (1), 21-39CODEN: NRDDAG; ISSN:1474-1776. (Nature Publishing Group)
      A review. Once a rarely used subset of medical treatments, protein therapeutics have increased dramatically in no. and frequency of use since the introduction of the first recombinant protein therapeutic - human insulin - 25 years ago. Protein therapeutics already have a significant role in almost every field of medicine, but this role is still only in its infancy. This article overviews some of the key characteristics of protein therapeutics, summarizes the more than 130 protein therapeutics used currently and suggests a new classification of these proteins according to their pharmacol. action.
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    29. 29
      Suntharalingam, G.; Perry, M. R.; Ward, S.; Brett, S. J.; Panoskaltsis, N. Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412. N. Engl. J. Med. 2006, 355, 1018– 1028,  DOI: 10.1056/NEJMoa063842
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      Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412
      Suntharalingam, Ganesh; Perry, Meghan R.; Ward, Stephen; Brett, Stephen J.; Castello-Cortes, Andrew; Brunner, Michael D.; Panoskaltsis, Nicki
      New England Journal of Medicine (2006), 355 (10), 1018-1028CODEN: NEJMAG; ISSN:0028-4793. (Massachusetts Medical Society)
      Six healthy young male volunteers at a contract research organization were enrolled in the first phase 1 clin. trial of TGN1412, a novel superagonist anti-CD28 monoclonal antibody that directly stimulates T cells. Within 90 min after receiving a single i.v. dose of the drug, all six volunteers had a systemic inflammatory response characterized by a rapid induction of proinflammatory cytokines and accompanied by headache, myalgias, nausea, diarrhea, erythema, vasodilatation, and hypotension. Within 12 to 16 h after infusion, they became critically ill, with pulmonary infiltrates and lung injury, renal failure, and disseminated intravascular coagulation. Severe and unexpected depletion of lymphocytes and monocytes occurred within 24 h after infusion. All six patients were transferred to the care of the authors at an intensive care unit at a public hospital, where they received intensive cardiopulmonary support (including dialysis), high-dose methylprednisolone, and an anti-interleukin-2 receptor antagonist antibody. Prolonged cardiovascular shock and acute respiratory distress syndrome developed in two patients, who required intensive organ support for 8 and 16 days. Despite evidence of the multiple cytokine-release syndrome, all six patients survived. Documentation of the clin. course occurring over the 30 days after infusion offers insight into the systemic inflammatory response syndrome in the absence of contaminating pathogens, endotoxin, or underlying disease.
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    30. 30
      Wadman, M. London’s disastrous drug trial has serious side effects for research. Nature 2006, 440, 388– 389,  DOI: 10.1038/440388a
      30
      London's disastrous drug trial has serious side effects for research
      Wadman, Meredith
      Nature (London, United Kingdom) (2006), 440 (7083), 388-389CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)
      There is no expanded citation for this reference.
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    31. 31
      Huck, B. R.; Kötzner, L.; Urbahns, K. Small molecules drive big improvements in immuno-oncology therapies. Angew. Chem., Int. Ed. 2018, 57, 4412– 4428,  DOI: 10.1002/anie.201707816
      31
      Small Molecules Drive Big Improvements in Immuno-Oncology Therapies
      Huck, Bayard R.; Koetzner, Lisa; Urbahns, Klaus
      Angewandte Chemie, International Edition (2018), 57 (16), 4412-4428CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
      A review. Immunooncol. therapies have the potential to revolutionize the armamentarium of available cancer treatments. To further improve clin. response rates, researchers are looking for novel combination regimens, with checkpoint blockade being used as a backbone of the treatment. This Review highlights the significance of small mols. in this approach, which holds promise to provide increased benefit to cancer patients.
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    32. 32
      Gadek, T. R.; Burdick, D. J.; McDowell, R. S.; Stanley, M. S. Generation of an LFA-1 antagonist by the transfer of the ICAM-1 immunoregulatory epitope to a small molecule. Science 2002, 295, 1086– 1089,  DOI: 10.1126/science.295.5557.1086
      32
      Generation of an LFA-1 antagonist by the transfer of the ICAM-1 immunoregulatory epitope to a small molecule
      Gadek, T. R.; Burdick, D. J.; McDowell, R. S.; Stanley, M. S.; Marsters, J. C., Jr.; Paris, K. J.; Oare, D. A.; Reynolds, M. E.; Ladner, C.; Zioncheck, K. A.; Lee, W. P.; Gribling, P.; Dennis, M. S.; Skelton, N. J.; Tumas, D. B.; Clark, K. R.; Keating, S. M.; Beresini, M. H.; Tilley, J. W.; Presta, L. G.; Bodary, S. C.
      Science (Washington, DC, United States) (2002), 295 (5557), 1086-1089CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)
      The protein-protein interaction between leukocyte functional antigen-1 (LFA-1) and intercellular adhesion mol.-1 (ICAM-1) is crit. to lymphocyte and immune system function. Here, we report on the transfer of the contiguous, nonlinear epitope of ICAM-1, responsible for its assocn. with LFA-1, to a small-mol. framework. These LFA-1 antagonists bound LFA-1, blocked binding of ICAM-1, and inhibited a mixed lymphocyte reaction (MLR) with potency significantly greater than that of cyclosporine A. Furthermore, in comparison to an antibody to LFA-1, they exhibited significant anti-inflammatory effects in vivo. These results demonstrate the utility of small-mol. mimics of nonlinear protein epitopes and the protein epitopes themselves as leads in the identification of novel pharmaceutical agents.
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    33. 33
      Scott, D. E.; Bayly, A. R.; Abell, C.; Skidmore, J. Small molecules, big targets: drug discovery faces the protein-protein interaction challenge. Nat. Rev. Drug Discovery 2016, 15, 533– 550,  DOI: 10.1038/nrd.2016.29
      33
      Small molecules, big targets: drug discovery faces the protein-protein interaction challenge
      Scott, Duncan E.; Bayly, Andrew R.; Abell, Chris; Skidmore, John
      Nature Reviews Drug Discovery (2016), 15 (8), 533-550CODEN: NRDDAG; ISSN:1474-1776. (Nature Publishing Group)
      Protein-protein interactions (PPIs) are of pivotal importance in the regulation of biol. systems and are consequently implicated in the development of disease states. Recent work has begun to show that, with the right tools, certain classes of PPI can yield to the efforts of medicinal chemists to develop inhibitors, and the first PPI inhibitors have reached clin. development. In this Review, we describe the research leading to these breakthroughs and highlight the existence of groups of structurally related PPIs within the PPI target class. For each of these groups, we use examples of successful discovery efforts to illustrate the research strategies that have proved most useful.
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    34. 34
      Zhang, G.; Pomplun, S.; Loftis, A. R.; Loas, A.; Pentelute, B. L. Investigation of ACE2 N-terminal fragments binding to SARS-CoV-2 spike RBD. bioRxiv , June 17, 2020, ver. 1.  DOI: 10.1101/2020.03.19.999318 .
      There is no corresponding record for this reference.
    35. 35
      Han, Y.; Král, P. Computational design of ACE2-based peptide inhibitors of SARS-CoV-2. ACS Nano 2020, 14, 5143– 5147,  DOI: 10.1021/acsnano.0c02857
      35
      Computational design of ACE2-based peptide inhibitors of SARS-CoV-2
      Han, Yanxiao; Kral, Petr
      ACS Nano (2020), 14 (4), 5143-5147CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society)
      Peptide inhibitors against the SARS-CoV-2 coronavirus, currently causing a worldwide pandemic, are designed and simulated. The inhibitors are mostly formed by two sequential self-supporting α-helixes (bundle) extd. from the protease domain (PD) of angiotensin-converting enzyme 2 (ACE2), which bind to the SARS-CoV-2 receptor binding domains. Mol. dynamics simulations revealed that the α-helical peptides maintain their secondary structure and provide a highly specific and stable binding (blocking) to SARS-CoV-2. To provide a multivalent binding to the SARS-CoV-2 receptors, many such peptides could be attached to the surfaces of nanoparticle carriers. The proposed peptide inhibitors could provide simple and efficient therapeutics against the COVID-19 disease.
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    36. 36
      Karoyan, P.; Vieillard, V.; Gómez-Morales, L. Human ACE2 peptide-mimics block SARS-CoV-2 pulmonary cells infection. Commun. Biol. 2021, 4, 197,  DOI: 10.1038/s42003-021-01736-8
      36
      Human ACE2 peptide-mimics block SARS-CoV-2 pulmonary cells infection
      Karoyan, Philippe; Vieillard, Vincent; Gomez-Morales, Luis; Odile, Estelle; Guihot, Amelie; Luyt, Charles-Edouard; Denis, Alexis; Grondin, Pascal; Lequin, Olivier
      Communications Biology (2021), 4 (1), 197CODEN: CBOIDQ; ISSN:2399-3642. (Nature Research)
      In light of the recent accumulated knowledge on SARS-CoV-2 and its mode of human cells invasion, the binding of viral spike glycoprotein to human Angiotensin Converting Enzyme 2 (hACE2) receptor plays a central role in cell entry. We designed a series of peptides mimicking the N-terminal helix of hACE2 protein which contains most of the contacting residues at the binding site, exhibiting a high helical folding propensity in aq. soln. Our best peptide-mimics are able to block SARS-CoV-2 human pulmonary cell infection with an inhibitory concn. (IC50) in the nanomolar range upon binding to the virus spike protein with high affinity. These first-in-class blocking peptide mimics represent powerful tools that might be used in prophylactic and therapeutic approaches to fight the coronavirus disease 2019 (COVID-19).
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    37. 37
      Curreli, F.; Victor, S. M. B.; Ahmed, S.; Drelich, A. Stapled peptides based on human angiotensin-converting enzyme 2 (ACE2) potently inhibit SARS-CoV-2 infection in vitro. mBio 2020, 11, e02451-20  DOI: 10.1128/mBio.02451-20
      There is no corresponding record for this reference.
    38. 38
      Tai, W. Identification of SARS-CoV RBD-targeting monoclonal antibodies with cross-reactive or neutralizing activity against SARS-CoV-2. Antiviral Res. 2020, 179, 104820,  DOI: 10.1016/j.antiviral.2020.104820
      38
      Identification of SARS-CoV RBD-targeting monoclonal antibodies with cross-reactive or neutralizing activity against SARS-CoV-2
      Tai, Wanbo; Zhang, Xiujuan; He, Yuxian; Jiang, Shibo; Du, Lanying
      Antiviral Research (2020), 179 (), 104820CODEN: ARSRDR; ISSN:0166-3542. (Elsevier B.V.)
      SARS-CoV-2-caused COVID-19 cases are growing globally, calling for developing effective therapeutics to control the current pandemic. SARS-CoV-2 and SARS-CoV recognize angiotensin-converting enzyme 2 (ACE2) receptor via the receptor-binding domain (RBD). Here, we identified six SARS-CoV RBD-specific neutralizing monoclonal antibodies (nAbs) that cross-reacted with SARS-CoV-2 RBD, two of which, 18F3 and 7B11, neutralized SARS-CoV-2 infection. 18F3 recognized conserved epitopes on SARS-CoV and SARS-CoV-2 RBDs, whereas 7B11 recognized epitopes on SARS-CoV RBD not fully conserved in SARS-CoV-2 RBD. The 18F3-recognizing epitopes on RBD did not overlap with the ACE2-binding sites, whereas those recognized by 7B11 were close to the ACE2-binding sites, explaining why 7B11 could, but 18F3 could not, block SARS-CoV or SARS-CoV-2 RBD binding to ACE2 receptor. Our study provides an alternative approach to prevent SARS-CoV-2 infection using anti-SARS-CoV nAbs.
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    39. 39
      De Vries, R. D.; Schmitz, K. S.; Bovier, F. T. Intranasal fusion inhibitory lipopeptide prevents direct contact SARS-CoV-2 transmission in ferrets. bioRxiv , November 5, 2020, ver. 1.  DOI: 10.1101/2020.11.04.361154 .
      There is no corresponding record for this reference.
    40. 40
      Tai, W.; He, L.; Zhang, X.; Pu, J.; Voronin, D.; Jiang, S.; Zhou, Y.; Du, L. Characterization of the receptor-binding domain (RBD) of 2019 novel coronavirus: implication for development of RBD protein as a viral attachment inhibitor and vaccine. Cell. Mol. Immunol. 2020, 17, 613– 620,  DOI: 10.1038/s41423-020-0400-4
      40
      Characterization of the receptor-binding domain (RBD) of 2019 novel coronavirus: implication for development of RBD protein as a viral attachment inhibitor and vaccine
      Tai, Wanbo; He, Lei; Zhang, Xiujuan; Pu, Jing; Voronin, Denis; Jiang, Shibo; Zhou, Yusen; Du, Lanying
      Cellular & Molecular Immunology (2020), 17 (6), 613-620CODEN: CMIEAO; ISSN:1672-7681. (Nature Research)
      The outbreak of Coronavirus Disease 2019 (COVID-19) has posed a serious threat to global public health, calling for the development of safe and effective prophylactics and therapeutics against infection of its causative agent, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), also known as 2019 novel coronavirus (2019-nCoV). The CoV spike (S) protein plays the most important roles in viral attachment, fusion and entry, and serves as a target for development of antibodies, entry inhibitors and vaccines. Here, we identified the receptor-binding domain (RBD) in SARS-CoV-2 S protein and found that the RBD protein bound strongly to human and bat angiotensin-converting enzyme 2 (ACE2) receptors. SARS-CoV-2 RBD exhibited significantly higher binding affinity to ACE2 receptor than SARS-CoV RBD and could block the binding and, hence, attachment of SARS-CoV-2 RBD and SARS-CoV RBD to ACE2-expressing cells, thus inhibiting their infection to host cells. SARS-CoV RBD-specific antibodies could cross-react with SARS-CoV-2 RBD protein, and SARS-CoV RBD-induced antisera could cross-neutralize SARS-CoV-2, suggesting the potential to develop SARS-CoV RBD-based vaccines for prevention of SARS-CoV-2 and SARS-CoV infection.
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    41. 41
      Sun, C.; Chen, L.; Yang, J. SARS-CoV-2 and SARS-CoV spike-RBD structure and receptor binding comparison and potential implications on neutralizing antibody and vaccine development. bioRxiv , February 20, 2020, ver. 1.  DOI: 10.1101/2020.02.16.951723 .
      There is no corresponding record for this reference.
    42. 42
      Xia, S.; Yan, L.; Xu, W.; Agrawal, A. S.; Algaissi, A.; Tseng, C. K.; Wang, Q.; Du, L.; Tan, W.; Wilson, I. A.; Jiang, S.; Yang, B.; Lu, L. A pan-coronavirus fusion inhibitor targeting the HR1mdomain of human coronavirus spike. Sci. Adv. 2019, 5, eaav4580  DOI: 10.1126/sciadv.aav4580
      There is no corresponding record for this reference.
    43. 43
      Rathod, S. B.; Prajapati, P. B.; Punjabi, L. B.; Prajapati, K. N.; Chauhan, N.; Mansuri, M. F. Peptide modelling and screening against human ACE2 and spike glycoprotein RBD of SARS CoV 2. In Silico Pharmacol. 2020, 8, 3,  DOI: 10.1007/s40203-020-00055-w
      43
      Peptide modelling and screening against human ACE2 and spike glycoprotein RBD of SARS-CoV-2
      Rathod Shravan B; Prajapati Pravin B; Prajapati Kuntal N; Punjabi Lata B; Chauhan Neha; Mansuri Mohmedyasin F
      In silico pharmacology (2020), 8 (1), 3 ISSN:2193-9616.
      Outbreak of Coronavirus Disease 2019 (COVID-19) has become a great challenge for scientific community globally. Virus enters cell through spike glycoprotein fusion with ACE2 (Angiotensin-Converting Enzyme 2) human receptor. Hence, spike glycoprotein of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a potential target for diagnostics, vaccines, and antibodies. Also, virus entry can be prevented by blocking ACE2 thus, ACE2 can be considered potential target for therapeutics. As being highly specific, safe and efficacious, peptides hold their place in therapeutics. In present study, we retrieved sequence of 70 peptides from Antiviral Peptide Database (AVPdb), modelled them using 3D structure predicting web tool and docked them with receptor binding domain (RBD) of spike protein and human host receptor ACE2 using peptide-protein docking. It was observed that peptides have more affinity towards ACE2 in comparison with spike RBD. Interestingly it was noticed that most of the peptides bind to RBM (residue binding motif) which is responsible for ACE2 binding at the interface of RBD while, for ACE2, peptides prefer to bind the core cavity rather than RBD binding interface. To further investigate how peptides at the interface of RBD or ACE2 alter the binding between RBD and ACE2, protein-protein docking of RBD and ACE2 with and without peptides was performed. Peptides, AVP0671 at RBD and AVP1244 at ACE2 interfaces significantly reduce the binding affinity and change the orientation of RBD and ACE2 binding. This finding suggests that peptides can be used as a drug to inhibit virus entry in cells to stop COVID-19 pandemic in the future after experimental evidences.
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    44. 44
      Watson, A.; Ferreira, L.; Hwang, P.; Xu, J.; Stroud, R. Peptide antidotes to SARS-CoV-2 (COVID-19). bioRxiv , August 6, 2020, ver. 1.  DOI: 10.1101/2020.08.06.238915 .
      There is no corresponding record for this reference.
    45. 45
      Singh, A.; Thakur, M.; Sharma, L. K.; Chandra, K. Designing a multi epitope peptide based vaccine against SARS CoV 2. Sci. Rep. 2020, 10, 16219,  DOI: 10.1038/s41598-020-73371-y
      45
      Designing a multi-epitope peptide based vaccine against SARS-CoV-2
      Singh, Abhishek; Thakur, Mukesh; Sharma, Lalit Kumar; Chandra, Kailash
      Scientific Reports (2020), 10 (1), 16219CODEN: SRCEC3; ISSN:2045-2322. (Nature Research)
      COVID-19 pandemic has resulted in 16,114,449 cases with 646,641 deaths from the 217 countries, or territories as on July 27th 2020. Due to multifaceted issues and challenges in the implementation of the safety and preventive measures, inconsistent coordination between societies-governments and most importantly lack of specific vaccine to SARS-CoV-2, the spread of the virus that initially emerged at Wuhan is still uprising after taking a heavy toll on human life. In the present study, we mapped immunogenic epitopes present on the four structural proteins of SARS-CoV-2 and we designed a multi-epitope peptide based vaccine that, demonstrated a high immunogenic response with a vast application on world's human population. On codon optimization and in-silico cloning, we found that candidate vaccine showed high expression in E. coli and immune simulation resulted in inducing a high level of both B-cell and T-cell mediated immunity. The results predicted that exposure of vaccine by administrating three injections significantly subsidized the antigen growth in the system. The proposed candidate vaccine found promising by yielding desired results and hence, should be validated by practical experimentations for its functioning and efficacy to neutralize SARS-CoV-2.
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    46. 46
      Molina, R.; Oliva, B.; Fernandez-Fuentes, N. A collection of designed peptides to target SARS-Cov-2 – ACE2 interaction: PepI-Covid19 database. bioRxiv , April 29, 2020, ver. 1.  DOI: 10.1101/2020.04.28.051789 .
      There is no corresponding record for this reference.
    47. 47
      Zhao, H.; To, K. K. W.; Sze, K. H.; Yung, T. T.; Bian, M.; Lam, H.; Yeung, M. L.; Li, C.; Chu, H.; Yuen, K. Y. A broad-spectrum virus- and host-targeting peptide against respiratory viruses including influenza virus and SARS-CoV-2. Nat. Commun. 2020, 11, 4252,  DOI: 10.1038/s41467-020-17986-9
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      A broad-spectrum virus- and host-targeting peptide against respiratory viruses including influenza virus and SARS-CoV-2
      Zhao, Hanjun; To, Kelvin K. W.; Sze, Kong-Hung; Yung, Timothy Tin-Mong; Bian, Mingjie; Lam, Hoiyan; Yeung, Man Lung; Li, Cun; Chu, Hin; Yuen, Kwok-Yung
      Nature Communications (2020), 11 (1), 4252CODEN: NCAOBW; ISSN:2041-1723. (Nature Research)
      The 2019 novel respiratory virus (SARS-CoV-2) causes COVID-19 with rapid global socioeconomic disruptions and disease burden to healthcare. The COVID-19 and previous emerging virus outbreaks highlight the urgent need for broad-spectrum antivirals. A defensin-like peptide P9R exhibited potent antiviral activity against pH-dependent viruses that require endosomal acidification for virus infection, including the enveloped pandemic A(H1N1)pdm09 virus, avian influenza A(H7N9) virus, coronaviruses (SARS-CoV-2, MERS-CoV and SARS-CoV), and the non-enveloped rhinovirus. P9R can significantly protect mice from lethal challenge by A(H1N1)pdm09 virus and shows low possibility to cause drug-resistant virus. Mechanistic studies indicate that the antiviral activity of P9R depends on the direct binding to viruses and the inhibition of virus-host endosomal acidification, which provides a proof of concept that virus-binding alk. peptides can broadly inhibit pH-dependent viruses. These results suggest that the dual-functional virus- and host-targeting P9R can be a promising candidate for combating pH-dependent respiratory viruses.
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    48. 48
      Han, D. P.; Penn-Nicholson, A.; Cho, M. W. Identification of critical determinants on ACE2 for SARS-CoV entry and development of a potent entry inhibitor. Virology 2006, 350 (1), 15– 25,  DOI: 10.1016/j.virol.2006.01.029
      48
      Identification of critical determinants on ACE2 for SARS-CoV entry and development of a potent entry inhibitor
      Han, Dong P.; Penn-Nicholson, Adam; Cho, Michael W.
      Virology (2006), 350 (1), 15-25CODEN: VIRLAX; ISSN:0042-6822. (Elsevier)
      Severe acute respiratory syndrome (SARS) is caused by a novel coronavirus, SARS-CoV. Virus entry into cells is mediated through interactions between spike (S) glycoprotein and angiotensin-converting enzyme 2 (ACE2). Alanine scanning mutagenesis anal. was performed to identify determinants on ACE2 crit. for SARS-CoV infection. Results indicated that charged amino acids between residues 22 and 57 were important, K26 and D30, in particular. Peptides representing various regions of ACE2 crit. for virus infection were chem. synthesized and evaluated for antiviral activity. Two peptides (a.a. 22-44 and 22-57) exhibited a modest antiviral activity with IC50 of about 50 μM and 6 μM, resp. One peptide comprised of two discontinuous segments of ACE2 (a.a. 22-44 and 351-357) artificially linked together by glycine, exhibited a potent antiviral activity with IC50 of about 0.1 μM. This novel peptide is a promising candidate as a therapeutic agent against this deadly emerging pathogen.
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    49. 49
      Shang, J.; Ye, G.; Shi, K.; Wan, Y.; Luo, C.; Aihara, H.; Geng, Q.; Auerbach, A.; Li, F. Structural basis of receptor recognition by SARS-CoV-2. Nature 2020, 581, 221– 224,  DOI: 10.1038/s41586-020-2179-y
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      Structural basis of receptor recognition by SARS-CoV-2
      Shang, Jian; Ye, Gang; Shi, Ke; Wan, Yushun; Luo, Chuming; Aihara, Hideki; Geng, Qibin; Auerbach, Ashley; Li, Fang
      Nature (London, United Kingdom) (2020), 581 (7807), 221-224CODEN: NATUAS; ISSN:0028-0836. (Nature Research)
      Abstr.: A novel severe acute respiratory syndrome (SARS)-like coronavirus (SARS-CoV-2) recently emerged and is rapidly spreading in humans, causing COVID-191,2. A key to tackling this pandemic is to understand the receptor recognition mechanism of the virus, which regulates its infectivity, pathogenesis and host range. SARS-CoV-2 and SARS-CoV recognize the same receptor-angiotensin-converting enzyme 2 (ACE2)-in humans3,4. Here we detd. the crystal structure of the receptor-binding domain (RBD) of the spike protein of SARS-CoV-2 (engineered to facilitate crystn.) in complex with ACE2. In comparison with the SARS-CoV RBD, an ACE2-binding ridge in SARS-CoV-2 RBD has a more compact conformation; moreover, several residue changes in the SARS-CoV-2 RBD stabilize two virus-binding hotspots at the RBD-ACE2 interface. These structural features of SARS-CoV-2 RBD increase its ACE2-binding affinity. Addnl., we show that RaTG13, a bat coronavirus that is closely related to SARS-CoV-2, also uses human ACE2 as its receptor. The differences among SARS-CoV-2, SARS-CoV and RaTG13 in ACE2 recognition shed light on the potential animal-to-human transmission of SARS-CoV-2. This study provides guidance for intervention strategies that target receptor recognition by SARS-CoV-2.
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    50. 50
      Zhou, T.; Tsybovsky, Y.; Gorman, J.; Rapp, M.; Cerutti, G. Cryo-EM structures of SARS-CoV-2 spike without and with ACE2 reveal a pH-dependent switch to mediate endosomal positioning of receptor-binding domains. Cell Host Microbe 2020, 28 (6), 867– 879,  DOI: 10.1016/j.chom.2020.11.004
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      Cryo-EM Structures of SARS-CoV-2 Spike without and with ACE2 Reveal a pH-Dependent Switch to Mediate Endosomal Positioning of Receptor-Binding Domains
      Zhou, Tongqing; Tsybovsky, Yaroslav; Gorman, Jason; Rapp, Micah; Cerutti, Gabriele; Chuang, Gwo-Yu; Katsamba, Phinikoula S.; Sampson, Jared M.; Schon, Arne; Bimela, Jude; Boyington, Jeffrey C.; Nazzari, Alexandra; Olia, Adam S.; Shi, Wei; Sastry, Mallika; Stephens, Tyler; Stuckey, Jonathan; Teng, I-Ting; Wang, Pengfei; Wang, Shuishu; Zhang, Baoshan; Friesner, Richard A.; Ho, David D.; Mascola, John R.; Shapiro, Lawrence; Kwong, Peter D.
      Cell Host & Microbe (2020), 28 (6), 867-879.e5CODEN: CHMECB; ISSN:1931-3128. (Elsevier Inc.)
      The SARS-CoV-2 spike employs mobile receptor-binding domains (RBDs) to engage the human ACE2 receptor and to facilitate virus entry, which can occur through low-pH-endosomal pathways. To understand how ACE2 binding and low pH affect spike conformation, we detd. cryo-electron microscopy structures-at serol. and endosomal pH-delineating spike recognition of up to three ACE2 mols. RBDs freely adopted "up" conformations required for ACE2 interaction, primarily through RBD movement combined with smaller alterations in neighboring domains. In the absence of ACE2, single-RBD-up conformations dominated at pH 5.5, resolving into a solitary all-down conformation at lower pH. Notably, a pH-dependent refolding region (residues 824-858) at the spike-interdomain interface displayed dramatic structural rearrangements and mediated RBD positioning through coordinated movements of the entire trimer apex. These structures provide a foundation for understanding prefusion-spike mechanics governing endosomal entry; we suggest that the low pH all-down conformation potentially facilitates immune evasion from RBD-up binding antibody.
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    51. 51
      Lan, J.; Ge, J.; Yu, J.; Shan, S.; Zhou, H.; Fan, S.; Zhang, Q.; Shi, X.; Wang, Q.; Zhang, L.; Wang, X. Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor. Nature 2020, 581, 215– 220,  DOI: 10.1038/s41586-020-2180-5
      51
      Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor
      Lan, Jun; Ge, Jiwan; Yu, Jinfang; Shan, Sisi; Zhou, Huan; Fan, Shilong; Zhang, Qi; Shi, Xuanling; Wang, Qisheng; Zhang, Linqi; Wang, Xinquan
      Nature (London, United Kingdom) (2020), 581 (7807), 215-220CODEN: NATUAS; ISSN:0028-0836. (Nature Research)
      Abstr.: A new and highly pathogenic coronavirus (severe acute respiratory syndrome coronavirus-2, SARS-CoV-2) caused an outbreak in Wuhan city, Hubei province, China, starting from Dec. 2019 that quickly spread nationwide and to other countries around the world1-3. Here, to better understand the initial step of infection at an at. level, we detd. the crystal structure of the receptor-binding domain (RBD) of the spike protein of SARS-CoV-2 bound to the cell receptor ACE2. The overall ACE2-binding mode of the SARS-CoV-2 RBD is nearly identical to that of the SARS-CoV RBD, which also uses ACE2 as the cell receptor4. Structural anal. identified residues in the SARS-CoV-2 RBD that are essential for ACE2 binding, the majority of which either are highly conserved or share similar side chain properties with those in the SARS-CoV RBD. Such similarity in structure and sequence strongly indicate convergent evolution between the SARS-CoV-2 and SARS-CoV RBDs for improved binding to ACE2, although SARS-CoV-2 does not cluster within SARS and SARS-related coronaviruses1-3,5. The epitopes of two SARS-CoV antibodies that target the RBD are also analyzed for binding to the SARS-CoV-2 RBD, providing insights into the future identification of cross-reactive antibodies.
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    52. 52
      Sadremomtaz, A.; Ali, A. M.; Jouyandeh, F.; Balalaie, S.; Navari, R. Molecular docking, synthesis and biological evaluation of vascular endothelial growth factor (VEGF) B based peptide as antiangiogenic agent targeting the second domain of the vascular endothelial growth factor receptor 1 (VEGFR1D2) for anticancer application. Sig. Transduct. Target Ther. 2020, 5, 76,  DOI: 10.1038/s41392-020-0177-z
      There is no corresponding record for this reference.
    53. 53
      Sadremomtaz, A.; Mansouri, K.; Alemzadeh, G.; Safa, M.; Rastaghi, A. E.; Asghari, S. M. Dual blockade of VEGFR1 and VEGFR2 by a novel peptide abrogates VEGF driven angiogenesis, tumor growth, and metastasis through PI3K/ AKT and MAPK/ERK1/2 pathway. Biochim. Biophys. Acta, Gen. Subj. 2018, 1862, 2688– 2700,  DOI: 10.1016/j.bbagen.2018.08.013
      53
      Dual blockade of VEGFR1 and VEGFR2 by a novel peptide abrogates VEGF-driven angiogenesis, tumor growth, and metastasis through PI3K/AKT and MAPK/ERK1/2 pathway
      Sadremomtaz, Afsaneh; Mansouri, Kamran; Alemzadeh, Golnaz; Safa, Majid; Rastaghi, Ahmadreza Esmaeili; Asghari, S. Mohsen
      Biochimica et Biophysica Acta, General Subjects (2018), 1862 (12), 2688-2700CODEN: BBGSB3; ISSN:0304-4165. (Elsevier B.V.)
      Neutralization of vascular endothelial growth factor receptor 1 (VEGFR1) and/or VEGFR2 is a widely used means of inhibiting tumor angiogenesis. Based on the complex X-ray structures of VEGFA/VEGFR1, VEGFA/VEGFR2, and VEGFB/VEGFR1, a peptide (referred to as VGB) was designed to simultaneously bind to VEGFR1 and VEGFR2, and binding, antiangiogenic and antitumor properties of the peptide was investigated in vitro. VGB bound to both VEGFR1 and VEGFR2 in human umbilical vein endothelial cells (HUVECs), and inhibited the proliferation of HUVECs, 4 T1 mammary carcinoma tumor (MCT) cells in human umbilical vein endothelial cells (HUVECs) and 4T1 mammary carcinoma tumor (MCT) cells, and inhibited the proliferation of HUVE, 4T1 MCT, and U87 glioblastoma cells. Through abrogation of AKT and ERK1/2 phosphorylation, VEGFA-stimulated proliferation, migration, and two- and three-dimensional tube formation in HUVECs were inhibited more potently by VGB than by bevacizumab. In a murine 4 T1 MCT model, VGB strongly inhibited tumor growth without causing wt. loss, accompanied by inhibition of AKT and ERK1/2 phosphorylation, a significant decrease in tumor cell proliferation (Ki-67 expression), angiogenesis (CD31 and CD34 expression), an increase in apoptosis index (increased TUNEL staining and p53 expression and decreased Bcl-2 expression), and the suppression of systematic spreading of the tumor (reduced NF-κB and MMP-9 and increased E-cadherin expression). The dual specificity of VGB for VEGFR1 and VEGFR2, through which the PI3K/AKT and MAPK/ERK1/2 signaling pathways can be abrogated and, subsequently, angiogenesis, tumor growth, and metastasis are inhibited. This study demonstrated that simultaneous blockade of VEGFR1 and VEGFR2 downstream cascades is an effective means for treatment of various angiogenic disorders, esp. cancer.
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    54. 54
      Sadremomtaz, A.; Kobarfard, F.; Mansouri, K.; Mirzanejad, L.; Asghari, S. M. Suppression of migratory and metastatic pathways via blocking VEGFR1 and VEGFR2. J. Recept. Signal Transduction Res. 2018, 38, 432– 441,  DOI: 10.1080/10799893.2019.1567785
      54
      Suppression of migratory and metastatic pathways via blocking VEGFR1 and VEGFR2
      Sadremomtaz Afsaneh; Mirzanejad Laleh; Asghari S Mohsen; Kobarfard Farzad; Mansouri Kamran
      Journal of receptor and signal transduction research (2018), 38 (5-6), 432-441 ISSN:.
      BACKGROUND: Vascular endothelial growth factor (VEGF) A and B are endothelial cell mitogens whose ligation to VEGFR1/VEGFR2 drives tumor angiogenesis and metastasis, and epithelial-mesenchymal transition (EMT). Blockade of these signaling axes could be obtained by disturbing the interactions between VEGFA and/or VEGFB with VEGFR1 and/or VEGFR2. METHODS: A 14-mer peptide (VGB) that recognizes both VEGFR1 and VEGFR2 were investigated for its inhibitory effects on the VEGF-induced proliferation and migration using MTT and scratch assay, respectively. Downstream signaling pathways were also assessed by quantitative estimation of gene and protein expression using real-time PCR and immunohistochemistry (IHC). RESULTS: We investigated the inhibitory effects of VGB on downstream mediators of metastasis, including epithelial-cadherin (E-cadherin), matrix metalloprotease-9 (MMP-9), cancer myelocytomatosis (c-Myc), and nuclear factor-κβ (NF-κβ), and migration, comprising focal adhesion kinase (FAK) and its substrate Paxilin. VGB inhibited the VEGF-induced proliferation of human umbilical vein endothelial cells (HUVECs), 4T1 and U87 cells in a time- and dose-dependent manner and migration of HUVECs. Based on IHC analyses, treatment of 4T1 mammary carcinoma tumor with VGB led to the suppression of p-AKT, p-ERK1/2, MMP-9, NF-κβ, and activation of E-cadherin compared with PBS-treated controls. Moreover, quantitative real-time PCR analyses of VGB-treated tumors revealed the reduced expression level of FAK, Paxilin, NF-κβ, MMP-9, c-Myc, and increased expression level of E-cadherin compared to PBS-treated controls. CONCLUSIONS: Our results demonstrated that simultaneous blockade of VEGFR1/VEGFR2 is an effective strategy to fight solid tumors by targeting a wider range of mediators involved in tumor angiogenesis, growth, and metastasis.
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    55. 55
      Abraham, M. J.; Murtola, T.; Schulz, R.; Pall, S.; Smith, J. C.; Hess, B.; Lindahl, E. GROMACS: High performance molecular simulations through multi-level parallelism from laptops to supercomputers. SoftwareX. 2015, 1 (2), 19– 25,  DOI: 10.1016/j.softx.2015.06.001
      There is no corresponding record for this reference.
    56. 56
      Jo, S.; Kim, T.; Iyer, V. G.; Im, W. CHARMM-GUI: a web-based graphical user interface for CHARMM. J. Comput. Chem. 2008, 29, 1859– 1865,  DOI: 10.1002/jcc.20945
      56
      CHARMM-GUI: a web-based graphical user interface for CHARMM
      Jo, Sunhwan; Kim, Taehoon; Iyer, Vidyashankara G.; Im, Wonpil
      Journal of Computational Chemistry (2008), 29 (11), 1859-1865CODEN: JCCHDD; ISSN:0192-8651. (John Wiley & Sons, Inc.)
      CHARMM is an academic research program used widely for macromol. mechanics and dynamics with versatile anal. and manipulation tools of at. coordinates and dynamics trajectories. CHARMM-GUI, http://www.charmm-gui.org, has been developed to provide a web-based graphical user interface to generate various input files and mol. systems to facilitate and standardize the usage of common and advanced simulation techniques in CHARMM. The web environment provides an ideal platform to build and validate a mol. model system in an interactive fashion such that, if a problem is found through visual inspection, one can go back to the previous setup and regenerate the whole system again. In this article, we describe the currently available functional modules of CHARMM-GUI Input Generator that form a basis for the advanced simulation techniques. Future directions of the CHARMM-GUI development project are also discussed briefly together with other features in the CHARMM-GUI website, such as Archive and Movie Gallery.
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    57. 57
      Gowers, R. J.; Linke, M.; Barnoud, J.; Reddy, T. J. E.; Melo, M. N.; Seyler, S. MDanalysis: a python package for the rapid analysis of molecular dynamics simulations. Proceedings of the 15th python in science conference 2016, 98– 105,  DOI: 10.25080/Majora-629e541a-00e
      There is no corresponding record for this reference.
    58. 58
      Salentin, S.; Schreiber, S.; Haupt, V. J.; Adasme, M. F.; Schroeder, M. PLIP: fully automated protein–ligand interaction profiler. Nucleic Acids Res. 2015, 43, W443– W447,  DOI: 10.1093/nar/gkv315
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      PLIP: fully automated protein-ligand interaction profiler
      Salentin, Sebastian; Schreiber, Sven; Haupt, V. Joachim; Adasme, Melissa F.; Schroeder, Michael
      Nucleic Acids Research (2015), 43 (W1), W443-W447CODEN: NARHAD; ISSN:0305-1048. (Oxford University Press)
      The characterization of interactions in protein-ligand complexes is essential for research in structural bioinformatics, drug discovery and biol. However, comprehensive tools are not freely available to the research community. Here, we present the protein-ligand interaction profiler (PLIP), a novel web service for fully automated detection and visualization of relevant non-covalent protein-ligand contacts in 3D structures, freely available at projects.biotec.tu-dresden.de/plip-web. The input is either a Protein Data Bank structure, a protein or ligand name, or a custom protein-ligand complex (e.g. from docking). In contrast to other tools, the rule-based PLIP algorithm does not require any structure prepn. It returns a list of detected interactions on single atom level, covering seven interaction types (hydrogen bonds, hydrophobic contacts, pi-stacking, pi-cation interactions, salt bridges, water bridges and halogen bonds). PLIP stands out by offering publication-ready images, PyMOL sesions files to generate custom images and parsable result files to facilitate successive data processing. The full python source code is available for download on the website. PLIP's command-line mode allows for high-throughput interaction profiling.
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    59. 59
      Kayikci, M.; Venkatakrishnan, A. J.; Scott-Brown, J. Visualization and analysis of non-covalent contacts using the protein contacts atlas. Nat. Struct. Mol. Biol. 2018, 25, 185– 194,  DOI: 10.1038/s41594-017-0019-z
      59
      Visualization and analysis of non-covalent contacts using the Protein Contacts Atlas
      Kayikci, Melis; Venkatakrishnan, A. J.; Scott-Brown, James; Ravarani, Charles N. J.; Flock, Tilman; Babu, M. Madan
      Nature Structural & Molecular Biology (2018), 25 (2), 185-194CODEN: NSMBCU; ISSN:1545-9993. (Nature Research)
      Visualizations of biomol. structures empower us to gain insights into biol. functions, generate testable hypotheses, and communicate biol. concepts. Typical visualizations (such as ball and stick) primarily depict covalent bonds. In contrast, non-covalent contacts between atoms, which govern normal physiol., pathogenesis, and drug action, are seldom visualized. We present the Protein Contacts Atlas, an interactive resource of non-covalent contacts from over 100,000 PDB crystal structures. We developed multiple representations for visualization and anal. of non-covalent contacts at different scales of organization: atoms, residues, secondary structure, subunits, and entire complexes. The Protein Contacts Atlas enables researchers from different disciplines to investigate diverse questions in the framework of non-covalent contacts, including the interpretation of allostery, disease mutations and polymorphisms, by exploring individual subunits, interfaces, and protein-ligand contacts and by mapping external information. The Protein Contacts Atlas is available at http://www.mrc-lmb.cam.ac.uk/pca/ and also through PDBe.
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    60. 60
      Azad, T.; Singaravelu, R.; Taha, Z.; Boulton, S. Nanoluciferase complementation-based biosensor reveals the importance of N- linked glycosylation of SARS-CoV-2 spike for viral entry. Mol. Ther. 2021, 29, 1984,  DOI: 10.1016/j.ymthe.2021.02.007
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      Nanoluciferase complementation-based bioreporter reveals the importance of N-linked glycosylation of SARS-CoV-2 S for viral entry
      Azad, Taha; Singaravelu, Ragunath; Taha, Zaid; Jamieson, Taylor R.; Boulton, Stephen; Crupi, Mathieu J. F.; Martin, Nikolas T.; Brown, Emily E. F.; Poutou, Joanna; Ghahremani, Mina; Pelin, Adrian; Nouri, Kazem; Rezaei, Reza; Marshall, Christopher Boyd; Enomoto, Masahiro; Arulanandam, Rozanne; Alluqmani, Nouf; Samson, Reuben; Gingras, Anne-Claude; Cameron, D. William; Greer, Peter A.; Ilkow, Carolina S.; Diallo, Jean-Simon; Bell, John C.
      Molecular Therapy (2021), 29 (6), 1984-2000CODEN: MTOHCK; ISSN:1525-0024. (Cell Press)
      The ongoing COVID-19 pandemic has highlighted the immediate need for the development of antiviral therapeutics targeting different stages of the SARS-CoV-2 life cycle. We developed a bioluminescence-based bioreporter to interrogate the interaction between the SARS-CoV-2 viral spike (S) protein and its host entry receptor, angiotensin-converting enzyme 2 (ACE2). The bioreporter assay is based on a nanoluciferase complementation reporter, composed of two subunits, large BiT and small BiT, fused to the S receptor-binding domain (RBD) of the SARS-CoV-2 S protein and ACE2 ectodomain, resp. Using this bioreporter, we uncovered crit. host and viral determinants of the interaction, including a role for glycosylation of asparagine residues within the RBD in mediating successful viral entry. We also demonstrate the importance of N-linked glycosylation to the RBD's antigenicity and immunogenicity. Our study demonstrates the versatility of our bioreporter in mapping key residues mediating viral entry as well as screening inhibitors of the ACE2-RBD interaction. Our findings point toward targeting RBD glycosylation for therapeutic and vaccine strategies against SARS-CoV-2.
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    61. 61
      Spiliotopoulos, D.; Kastritis, P. L.; Melquiond, A. S.; Bonvin, A. M.; Musco, G.; Rocchia, W.; Spitaleri, A. dMM-PBSA: A new HADDOCK scoring function for protein-peptide docking. Front Mol. Biosci. 2016, 3, 46,  DOI: 10.3389/fmolb.2016.00046
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      dMM-PBSA: a new HADDOCK scoring function for protein-peptide docking
      Spiliotopoulos, Dimitrios; Kastritis, Panagiotis L.; Melquiond, Adrien S. J.; Bonvin, Alexandre M. J. J.; Musco, Giovanna; Rocchia, Walter; Spitaleri, Andrea
      Frontiers in Molecular Biosciences (2016), 3 (), 46/1-46/13CODEN: FMBRBS; ISSN:2296-889X. (Frontiers Media S.A.)
      Mol.-docking programs coupled with suitable scoring functions are now established and very useful tools enabling computational chemists to rapidly screen large chem. databases and thereby to identify promising candidate compds. for further exptl. processing. In a broader scenario, predicting binding affinity is one of the most crit. and challenging components of computer-aided structure-based drug design. The development of a mol. docking scoring function which in principle could combine both features, namely ranking putative poses and predicting complex affinity, would be of paramount importance. Here, we systematically investigated the performance of the MM-PBSA approach, using two different Poisson-Boltzmann solvers (APBS and DelPhi), in the currently rising field of protein-peptide interactions (PPIs), identifying the correct binding conformations of 19 different protein-peptide complexes and predicting their binding free energies. First, we scored the decoy structures from HADDOCK calcn. via the MM-PBSA approach in order to assess the capability of retrieving near-native poses in the best-scoring clusters and of evaluating the corresponding free energies of binding. MM-PBSA behaves well in finding the poses corresponding to the lowest binding free energy. In order to improve the MM-PBSA-based scoring function, we dampened the MM-PBSA solvation and coulombic terms by 0.2, as proposed in the HADDOCK score and LIE approaches.
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    62. 62
      Li, W.; Zhang, C.; Sui, J.; Kuhn, J. H.; Moore, M. J.; Luo, S.; Wong, S. K.; Huang, I. C.; Xu, K.; Vasilieva, N.; Murakami, A.; He, Y.; Marasco, W. A.; Guan, Y.; Choe, H.; Farzan, M. Receptor and viral determinants of SARS-coronavirus adaptation to human ACE2. EMBO J. 2005, 24, 1634– 1643,  DOI: 10.1038/sj.emboj.7600640
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      Receptor and viral determinants of SARS-coronavirus adaptation to human ACE2
      Li, Wenhui; Zhang, Chengsheng; Sui, Jianhua; Kuhn, Jens H.; Moore, Michael J.; Luo, Shiwen; Wong, Swee-Kee; Huang, I-Chueh; Xu, Keming; Vasilieva, Natalya; Murakami, Akikazu; He, Yaqing; Marasco, Wayne A.; Guan, Yi; Choe, Hyeryun; Farzan, Michael
      EMBO Journal (2005), 24 (8), 1634-1643CODEN: EMJODG; ISSN:0261-4189. (Nature Publishing Group)
      Human angiotensin-converting enzyme 2 (ACE2) is a functional receptor for SARS coronavirus (SARS-CoV). Here we identify the SARS-CoV spike (S)-protein-binding site on ACE2. We also compare S proteins of SARS-CoV isolated during the 2002-2003 SARS outbreak and during the much less severe 2003-2004 outbreak, and from palm civets, a possible source of SARS-CoV found in humans. All three S proteins bound to and utilized palm-civet ACE2 efficiently, but the latter two S proteins utilized human ACE2 markedly less efficiently than did the S protein obtained during the earlier human outbreak. The lower affinity of these S proteins could be complemented by altering specific residues within the S-protein-binding site of human ACE2 to those of civet ACE2, or by altering S-protein residues 479 and 487 to residues conserved during the 2002-2003 outbreak. Collectively, these data describe mol. interactions important to the adaptation of SARS-CoV to human cells, and provide insight into the severity of the 2002-2003 SARS epidemic.
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    63. 63
      Elbe, S.; Buckland-Merrett, G. Data, disease and diplomacy: GISAID’s innovative contribution to global health. Global Challenges 2017, 1, 33,  DOI: 10.1002/gch2.1018
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      Data, disease and diplomacy: GISAID's innovative contribution to global health
      Elbe Stefan; Buckland-Merrett Gemma
      Global challenges (Hoboken, NJ) (2017), 1 (1), 33-46 ISSN:.
      The international sharing of virus data is critical for protecting populations against lethal infectious disease outbreaks. Scientists must rapidly share information to assess the nature of the threat and develop new medical countermeasures. Governments need the data to trace the extent of the outbreak, initiate public health responses, and coordinate access to medicines and vaccines. Recent outbreaks suggest, however, that the sharing of such data cannot be taken for granted - making the timely international exchange of virus data a vital global challenge. This article undertakes the first analysis of the Global Initiative on Sharing All Influenza Data as an innovative policy effort to promote the international sharing of genetic and associated influenza virus data. Based on more than 20 semi-structured interviews conducted with key informants in the international community, coupled with analysis of a wide range of primary and secondary sources, the article finds that the Global Initiative on Sharing All Influenza Data contributes to global health in at least five ways: (1) collating the most complete repository of high-quality influenza data in the world; (2) facilitating the rapid sharing of potentially pandemic virus information during recent outbreaks; (3) supporting the World Health Organization's biannual seasonal flu vaccine strain selection process; (4) developing informal mechanisms for conflict resolution around the sharing of virus data; and (5) building greater trust with several countries key to global pandemic preparedness.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3MnjtFKmug%253D%253D&md5=ec5a87c7612a5922dd7bd76718359f20
    64. 64
      Baskaran, K.; Duarte, J. M.; Biyani, N.; Bliven, S.; Capitani, G. A PDB-wide, evolution-based assessment of protein-protein interfaces. BMC Struct. Biol. 2014, 14, 1422,  DOI: 10.1186/s12900-014-0022-0
      There is no corresponding record for this reference.
    65. 65
      Amaral, M.; Kokh, D. B.; Bomke, J.; Wegener, A.; Buchstaller, H. P.; Eggenweiler, H. M. Protein conformational flexibility modulates kinetics and thermodynamics of drug binding. Nat. Commun. 2017, 8, 2276,  DOI: 10.1038/s41467-017-02258-w
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      Protein conformational flexibility modulates kinetics and thermodynamics of drug binding
      Amaral M; Matias P; Amaral M; Wegener A; Frech M; Amaral M; Kokh D B; Wade R C; Bomke J; Buchstaller H P; Eggenweiler H M; Matias P; Sirrenberg C; Wade R C; Wade R C
      Nature communications (2017), 8 (1), 2276 ISSN:.
      Structure-based drug design has often been restricted by the rather static picture of protein-ligand complexes presented by crystal structures, despite the widely accepted importance of protein flexibility in biomolecular recognition. Here we report a detailed experimental and computational study of the drug target, human heat shock protein 90, to explore the contribution of protein dynamics to the binding thermodynamics and kinetics of drug-like compounds. We observe that their binding properties depend on whether the protein has a loop or a helical conformation in the binding site of the ligand-bound state. Compounds bound to the helical conformation display slow association and dissociation rates, high-affinity and high cellular efficacy, and predominantly entropically driven binding. An important entropic contribution comes from the greater flexibility of the helical relative to the loop conformation in the ligand-bound state. This unusual mechanism suggests increasing target flexibility in the bound state by ligand design as a new strategy for drug discovery.
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    66. 66
      Ferina, J.; Daggett, V. Visualizing protein folding and unfolding. J. Mol. Biol. 2019, 431, 1540– 1564,  DOI: 10.1016/j.jmb.2019.02.026
      65
      Visualizing Protein Folding and Unfolding
      Ferina, Jennifer; Daggett, Valerie
      Journal of Molecular Biology (2019), 431 (8), 1540-1564CODEN: JMOBAK; ISSN:0022-2836. (Elsevier Ltd.)
      A review. Protein folding/unfolding is a complicated process that defies high-resoln. characterization by exptl. methods. As an alternative, atomistic mol. dynamics simulations are now routinely employed to elucidate and magnify the accompanying conformational changes and the role of solvent in the folding process. However, the level of detail necessary to map the process at high spatial-temporal resoln. provides an overwhelming amt. of data. As more and better tools are developed for anal. of these large data sets and validation of the simulations, one is still left with the problem of visualizing the results in ways that provide insight into the folding/unfolding process. While viewing and interrogating static crystal structures has become commonplace, more and different approaches are required for dynamic, interconverting, unfolding, and refolding proteins. Here the authors review a variety of approaches, ranging from straightforward to complex and unintuitive for multiscale anal. and visualization of protein folding and unfolding.
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    67. 67
      Zambrano, R.; Jamroz, M.; Szczasiuk, A.; Pujols, J.; Kmiecik, S.; Ventura, S. AGGRESCAN3D (A3D): server for prediction of aggregation properties of protein structures. Nucleic Acids Res. 2015, 43, W306– 313,  DOI: 10.1093/nar/gkv359
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      AGGRESCAN3D (A3D): server for prediction of aggregation properties of protein structures
      Zambrano, Rafael; Jamroz, Michal; Szczasiuk, Agata; Pujols, Jordi; Kmiecik, Sebastian; Ventura, Salvador
      Nucleic Acids Research (2015), 43 (W1), W306-W313CODEN: NARHAD; ISSN:0305-1048. (Oxford University Press)
      Protein aggregation underlies an increasing no. of disorders and constitutes a major bottleneck in the development of therapeutic proteins. Our present understanding on the mol. determinants of protein aggregation has crystd. in a series of predictive algorithms to identify aggregation-prone sites. A majority of these methods rely only on sequence. Therefore, they find difficulties to predict the aggregation properties of folded globular proteins, where aggregation-prone sites are often not contiguous in sequence or buried inside the native structure. The AGGRESCAN3D (A3D) server overcomes these limitations by taking into account the protein structure and the exptl. aggregation propensity scale from the well-established AGGRESCAN method. Using the A3D server, the identified aggregation-prone residues can be virtually mutated to design variants with increased soly., or to test the impact of pathogenic mutations. Addnl., A3D server enables to take into account the dynamic fluctuations of protein structure in soln., which may influence aggregation propensity. This is possible in A3D Dynamic Mode that exploits the CABS-flex approach for the fast simulations of flexibility of globular proteins.
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    68. 68
      Goel, B.; Bhardwaj, N.; Tripathi, N.; Jain, S. K. Drug discovery of small molecules for the treatment of COVID-19: a review on clinical studies. Mini-Rev. Med. Chem. 2021, 21, 1431,  DOI: 10.2174/1389557521666201228145755
      67
      Drug Discovery of Small Molecules for the Treatment of COVID-19: A Review on Clinical Studies
      Goel, Bharat; Bhardwaj, Nivedita; Tripathi, Nancy; Jain, Shreyans K.
      Mini-Reviews in Medicinal Chemistry (2021), 21 (12), 1431-1456CODEN: MMCIAE; ISSN:1389-5575. (Bentham Science Publishers Ltd.)
      A review. Recently, a sudden outbreak of novel coronavirus disease (COVID-19) was caused by a zoonotic virus known as severe acute respiratory syndrome coronavirus (SARS-CoV-2). It has caused pandemic situations around the globe affecting the lives of millions of people. So far, no drug has been approved for the treatment of SARS-CoV-2 infected patients. As of now, more than 1000 clin. trials are going on for repurposing of FDA-approved drugs and for evaluating the safety and efficiency of exptl. antiviral mols. to combat COVID-19. Since the development of new drugs may require months to years to reach the market, this review focusses on the potential of existing small mol. FDA approved drugs and the mols. already in the clin. pipeline against viral infections like HIV, hepatitis B, Ebola virus, and other viruses of coronavirus family (SARS-CoV and MERS-CoV). The review also discusses the natural products and traditional medicines in clin. studies against COVID-19. Currently, 1978 studies are active, 143 completed and 4 posted results (as of June 13, 2020) on clinicaltrials.gov.
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    69. 69
      Pant, S.; Singh, M.; Ravichandiran, V.; Murty, U. S. N.; Srivastava, H. K. Peptide-like and small-molecule inhibitors against COVID-19. J. Biomol. Struct. Dyn. 2021, 39, 2904,  DOI: 10.1080/07391102.2020.1757510
      68
      Peptide-like and small-molecule inhibitors against Covid-19
      Pant, Suyash; Singh, Meenakshi; Ravichandiran, V.; Murty, U. S. N.; Srivastava, Hemant Kumar
      Journal of Biomolecular Structure and Dynamics (2021), 39 (8), 2904-2913CODEN: JBSDD6; ISSN:0739-1102. (Taylor & Francis Ltd.)
      Coronavirus disease strain (SARS-CoV-2) was discovered in 2019, and it is spreading very fast around the world causing the disease Covid-19. Currently, >1.6 million individuals are infected, and several thousand are dead across the globe because of Covid-19. We utilized the in-silico approaches to identify possible protease inhibitors against SARS-CoV-2. Potential compds. were screened from the CHEMBL database, ZINC database, FDA approved drugs, and mols. under clin. trials. Our study is based on 6Y2F and 6W63 co-crystd. structures available in the protein data bank (PDB). Seven hundred compds. from ZINC/CHEMBL databases and 1400 compds. from drug-bank were selected based on pos. interactions with the reported binding site. All the selected compds. were subjected to std.-precision (SP) and extra-precision (XP) mode of docking. Generated docked poses were carefully visualized for known interactions within the binding site. Mol. mechanics-generalized born surface area (MM-GBSA) calcns. were performed to screen the best compds. based on docking scores and binding energy values. Mol. dynamics (MD) simulations were carried out on 4 selected compds. from the CHEMBL database to validate the stability and interactions. MD simulations were also performed on the PDB structure 6YF2F to understand the differences between screened mols. and co-crystd. ligand. We screened 300 potential compds. from various databases, and 66 potential compds. from FDA approved drugs. Cobicistat, ritonavir, lopinavir, and darunavir are in the top screened mols. from FDA approved drugs. The screened drugs and mols. may be helpful in fighting with SARS-CoV-2 after further studies.
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    70. 70
      Di Natale, C.; La Manna, S.; De Benedictis, I.; Brandi, P.; Marasco, D. Perspectives in peptide-based vaccination strategies for syndrome coronavirus 2 pandemic. Front. Pharmacol. 2020, 11, 578382,  DOI: 10.3389/fphar.2020.578382
      69
      Perspectives in peptide-based vaccination strategies for syndrome coronavirus 2 pandemic
      Di Natale, Concetta; La Manna, Sara; De Benedictis, Ilaria; Brandi, Paola; Marasco, Daniela
      Frontiers in Pharmacology (2020), 11 (), 578382CODEN: FPRHAU; ISSN:1663-9812. (Frontiers Media S.A.)
      At the end of Dec. 2019, an epidemic form of respiratory tract infection now named COVID-19 emerged in Wuhan, China. It is caused by a newly identified viral pathogen, the severe acute respiratory syndrome coronavirus (SARS-CoV-2), which can cause severe pneumonia and acute respiratory distress syndrome. On Jan. 30, 2020, due to the rapid spread of infection, COVID-19 was declared as a global health emergency by the World Health Organization. Coronaviruses are enveloped RNA viruses belonging to the family of Coronaviridae, which are able to infect birds, humans and other mammals. The majority of human coronavirus infections are mild although already in 2003 and in 2012, the epidemics of SARS-CoV and Middle East Respiratory Syndrome coronavirus (MERSCoV), resp., were characterized by a high mortality rate. In this regard, many efforts have been made to develop therapeutic strategies against human CoV infections but, unfortunately, drug candidates have shown efficacy only into in vitro studies, limiting their use against COVID-19 infection. Actually, no treatment has been approved in humans against SARS-CoV-2, and therefore there is an urgent need of a suitable vaccine to tackle this health issue. However, the puzzled scenario of biol. features of the virus and its interaction with human immune response, represent a challenge for vaccine development. As expected, in hundreds of research labs. there is a running out of breath to explore different strategies to obtain a safe and quickly spreadable vaccine; and among others, the peptide-based approach represents a turning point as peptides have demonstrated unique features of selectivity and specificity toward specific targets. Peptide-based vaccines imply the identification of different epitopes both on human cells and virus capsid and the design of peptide/peptidomimetics able to counteract the primary host-pathogen interaction, in order to induce a specific host immune response. SARS-CoV-2 immunogenic regions are mainly distributed, as well as for other coronaviruses, across structural areas such as spike, envelope, membrane or nucleocapsid proteins. Herein, we aim to highlight the mol. basis of the infection and recent peptide-based vaccines strategies to fight the COVID-19 pandemic including their delivery systems.
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    71. 71
      Pessi, A.; Bixler, S. L.; Soloveva, V.; Radoshitzky, S.; Retterer, C. Cholesterol-conjugated stapled peptides inhibit Ebola and Marburg viruses in vitro and in vivo. Antiviral Res. 2019, 171, 104592,  DOI: 10.1016/j.antiviral.2019.104592
      70
      Cholesterol-conjugated stapled peptides inhibit Ebola and Marburg viruses in vitro and in vivo
      Pessi, Antonello; Bixler, Sandra L.; Soloveva, Veronica; Radoshitzky, Sheli; Retterer, Cary; Kenny, Tara; Zamani, Rouzbeh; Gomba, Glenn; Gharabeih, Dima; Wells, Jay; Wetzel, Kelly S.; Warren, Travis K.; Donnelly, Ginger; Van Tongeren, Sean A.; Steffens, Jesse; Duplantier, Allen J.; Kane, Christopher D.; Vicat, Pascale; Couturier, Valerie; Kester, Kent E.; Shiver, John; Carter, Kara; Bavari, Sina
      Antiviral Research (2019), 171 (), 104592CODEN: ARSRDR; ISSN:0166-3542. (Elsevier B.V.)
      Currently, there are no therapeutics approved and the need for Ebola-specific therapeutics remains a gap. In search for anti-Ebola therapies we tested the idea of using inhibitory properties of peptides corresponding to the C-terminal heptad-repeat (HR2) domains of class I fusion proteins against EBOV infection. The fusion protein GP2 of EBOV belongs to class I, suggesting that a similar strategy to HIV may be applied to inhibit EBOV infection. The serum half-life of peptides was expanded by cholesterol conjugation to allow daily dosing. The peptides were further constrained to stabilize a helical structure to increase the potency of inhibition. The EC50s of lead peptides were in low micromolar range, as detd. by a high-content imaging test of EBOV-infected cells. Lead peptides were tested in an EBOV lethal mouse model and efficacy of the peptides were detd. following twice-daily administration of peptides for 9 days. The most potent peptide was able to protect mice from lethal challenge of mouse-adapted Ebola virus. These data show that engineered peptides coupled with cholesterol can inhibit viral prodn., protect mice against lethal EBOV infection, and may be used to build novel therapeutics against EBOV.
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    72. 72
      Li, C. G.; Tang, W.; Chi, X. J.; Dong, Z. M.; Wang, X. X.; Wang, X. J. A cholesterol tag at the N terminus of the relatively broad-spectrum fusion inhibitory peptide targets an earlier stage of fusion glycoprotein activation and increases the peptide’s antiviral potency in vivo. J. Virol. 2013, 87, 9223– 9232,  DOI: 10.1128/JVI.01153-13
      71
      A cholesterol tag at the N terminus of the relatively broad-spectrum fusion inhibitory peptide targets an earlier stage of fusion glycoprotein activation and increases the peptide's antiviral potency in vivo
      Li, Chuan-Gen; Wang, Tang; Chi, Xiao-Jing; Dong, Zhi-Ming; Wang, Xi-Xi; Wang, Xiao-Jia
      Journal of Virology (2013), 87 (16), 9223-9232CODEN: JOVIAM; ISSN:1098-5514. (American Society for Microbiology)
      In previous work, we designed peptides that showed potent inhibition of Newcastle disease virus (NDV) and infectious bronchitis virus (IBV) infections in chicken embryos. In this study, we demonstrate that peptides modified with cholesterol or 3 U of polyethylene glycol (PEG3) conjugated to the peptides' N termini showed even more promising antiviral activities when tested in animal models. Both cholesterol- and cholesterol-PEG3-tagged peptides were able to protect chicken embryos from infection with different serotypes of NDV and IBV when administered 12 h prior to virus inoculation. In comparison, the untagged peptides required intervention closer to the time of viral inoculation to achieve a similar level of protection. I.m. injection of cholesterol-tagged peptide at 1.6 mg/kg 1 day before virus infection and then three times at 3-day intervals after viral inoculation protected 70% of the chickens from NDV infection. We further demonstrate that the cholesterol-tagged peptide has an in vivo half-life greater than that of untagged peptides. It also has the potential to cross the blood-brain barrier to enter the avian central nervous system (CNS). Finally, we show that the cholesterol-tagged peptide could play a role before the viral fusion peptide's insertion into the host cell and thereby target an earlier stage of fusion glycoprotein activation. Our findings are of importance for the further development of antivirals with broad-spectrum protective effects.
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    73. 73
      Pessi, A. Cholesterol-conjugated peptide antivirals: a path to a rapid response to emerging viral diseases. J. Pept. Sci. 2015, 21, 379– 386,  DOI: 10.1002/psc.2706
      72
      Cholesterol-conjugated peptide antivirals: a path to a rapid response to emerging viral diseases
      Pessi, Antonello
      Journal of Peptide Science (2015), 21 (5), 379-386CODEN: JPSIEI; ISSN:1075-2617. (John Wiley & Sons Ltd.)
      A review. While it is now possible to identify and genetically fingerprint the causative agents of emerging viral diseases, often with extraordinary speed, suitable therapies cannot be developed with equiv. speed, because drug discovery requires information that goes beyond knowledge of the viral genome. Peptides, however, may represent a special opportunity. For all enveloped viruses, fusion between the viral and the target cell membrane is an obligatory step of the life cycle. Class I fusion proteins harbor regions with a repeating pattern of amino acids, the heptad repeats (HRs), that play a key role in fusion, and HR-derived peptides such as enfuvirtide, in clin. use for HIV, can block the process. Because of their characteristic sequence pattern, HRs are easily identified in the genome by means of computer programs, providing the sequence of candidate peptide inhibitors directly from genomic information. Moreover, a simple chem. modification, the attachment of a cholesterol group, can dramatically increase the antiviral potency of HR-derived inhibitors and simultaneously improve their pharmacokinetics. Further enhancement can be provided by dimerization of the cholesterol-conjugated peptide. The examples reported so far include inhibitors of retroviruses, paramyxoviruses, orthomyxoviruses, henipaviruses, coronaviruses, and filoviruses. For some of these viruses, in vivo efficacy has been demonstrated in suitable animal models. The combination of bioinformatic lead identification and potency/pharmacokinetics improvement provided by cholesterol conjugation may form the basis for a rapid response strategy, where development of an emergency cholesterol-conjugated therapeutic would immediately follow the availability of the genetic information of a new enveloped virus. Copyright © 2014 European Peptide Society and John Wiley & Sons, Ltd.
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    74. 74
      Pettersen, E. F.; Goddard, T. D.; Huang, C. C.; Couch, G. S.; Greenblatt, D. M.; Meng, E. C.; Ferrin, T. E. UCSF chimera--a visualization system for exploratory research and analysis. J. Comput. Chem. 2004, 25, 1605– 1612,  DOI: 10.1002/jcc.20084
      73
      UCSF Chimera-A visualization system for exploratory research and analysis
      Pettersen, Eric F.; Goddard, Thomas D.; Huang, Conrad C.; Couch, Gregory S.; Greenblatt, Daniel M.; Meng, Elaine C.; Ferrin, Thomas E.
      Journal of Computational Chemistry (2004), 25 (13), 1605-1612CODEN: JCCHDD; ISSN:0192-8651. (John Wiley & Sons, Inc.)
      The design, implementation, and capabilities of an extensible visualization system, UCSF Chimera, are discussed. Chimera is segmented into a core that provides basic services and visualization, and extensions that provide most higher level functionality. This architecture ensures that the extension mechanism satisfies the demands of outside developers who wish to incorporate new features. Two unusual extensions are presented: Multiscale, which adds the ability to visualize large-scale mol. assemblies such as viral coats, and Collab., which allows researchers to share a Chimera session interactively despite being at sep. locales. Other extensions include Multalign Viewer, for showing multiple sequence alignments and assocd. structures; ViewDock, for screening docked ligand orientations; Movie, for replaying mol. dynamics trajectories; and Vol. Viewer, for display and anal. of volumetric data. A discussion of the usage of Chimera in real-world situations is given, along with anticipated future directions. Chimera includes full user documentation, is free to academic and nonprofit users, and is available for Microsoft Windows, Linux, Apple Mac OS X, SGI IRIX, and HP Tru64 Unix from http://www.cgl.ucsf.edu/chimera/.
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    75. 75
      Caporale, A.; Doti, N.; Monti, A.; Sandomenico, A.; Ruvo, M. Automatic procedures for the synthesis of difficult peptides using oxyma as activating reagent: A comparative study on the use of bases and on different deprotection and agitation conditions. Peptides 2018, 102, 38– 46,  DOI: 10.1016/j.peptides.2018.02.006
      74
      Automatic procedures for the synthesis of difficult peptides using oxyma as activating reagent: A comparative study on the use of bases and on different deprotection and agitation conditions
      Caporale, A.; Doti, N.; Monti, A.; Sandomenico, A.; Ruvo, M.
      Peptides (New York, NY, United States) (2018), 102 (), 38-46CODEN: PPTDD5; ISSN:0196-9781. (Elsevier)
      Solid-Phase Peptide Synthesis (SPPS) is a rapid and efficient methodol. for the chem. synthesis of peptides and small proteins. However, the assembly of peptide sequences classified as "difficult" poses severe synthetic problems in SPPS for the occurrence of extensive aggregation of growing peptide chains which often leads to synthesis failure. In this framework, we have investigated the impact of different synthetic procedures on the yield and final purity of three well-known "difficult peptides" prepd. using oxyma as additive for the coupling steps. In particular, we have comparatively investigated the use of piperidine and morpholine/DBU as deprotection reagents, the addn. of DIPEA, collidine and N-methylmorpholine as bases to the coupling reagent. Moreover, the effect of different agitation modalities during the acylation reactions has been investigated. Data obtained represent a step forward in optimizing strategies for the synthesis of "difficult peptides".
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      Grimsley, G. R.; Pace, C. N. Spectrophotometric Determination of Protein Concentration. Curr. Protoc. Protein Sci. 2003, 3.1.1– 3.1.9,  DOI: 10.1002/0471140864.ps0301s33
      There is no corresponding record for this reference.
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      Scopes, R.K. Measurement of protein by spectrophotometry at 205 nm. Anal. Biochem. 1974, 59, 277– 282,  DOI: 10.1016/0003-2697(74)90034-7
      76
      Measurement of protein by spectrophotometry at 205nm
      Scopes, R. K.
      Analytical Biochemistry (1974), 59 (1), 277-82CODEN: ANBCA2; ISSN:0003-2697.
      A method was described for the measurement of protein concn. by using the peptide bond absorption at 205 nm. The extinction coeff. (ε) at 205 nm was estd., allowing for the absorption due to tryptophan and tyrosine residues, by measuring the absorbance at 280 nm as well as at 205 nm. The estd. ε205 was compared with the actual ε205 for a no. of proteins, the mean error being <2%. This was about 3 times better than using an av. ε2051mg/ml of 31 and approached the range of exptl. error inherent in any method of protein estn.
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  • Supporting Information

    Supporting Information

    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.jmedchem.1c00477.

    • Additional figures illustrating molecular interaction from MD analysis of designed peptides and S-RBD, binding free energy of ACE2 derived peptides in complexes of S-RBD (binding energies of ACE2:S-RBD included for comparison), peptide LC-MS characterization, details of changes in hot spot area plot caused by aggregation of peptides, variation of fluorescence peak intensity with increasing concentration of peptides, CD spectra of peptides, overlay of emission spectra of samples dissolved in PBS and PBST, 1% (w/v) PEG8000 at 25 μM in 2.5% DMSO, and SEC of peptides; additional tables detailing key interactions between S-RBD and ACE2 identified using PiPreD, peptide sequences including replacement of some residues for improved targeting of S-RBD, analysis of data collected for the calculation of concentration of peptides in PBS and PBST, 1% (w/v) PEG8000 by UV spectroscopy analysis, theoretical, apparent molecular weight, and Rt values of ACE2-antagonist peptides as determined by SEC analysis, and dose–response results of the antiviral activity of peptides in a SARS-CoV-2 infection inhibition assay performed in VERO-E6 cells (PDF)


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