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Targeting SARS-CoV-2 Receptor Binding Domain with Stapled Peptides: An In Silico Study

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Download Hi-Res ImageDownload to MS-PowerPointCite This:J. Phys. Chem. B 2021, 125, 24, 6572-6586
    B: Biomaterials and Membranes

    Targeting SARS-CoV-2 Receptor Binding Domain with Stapled Peptides: An In Silico Study
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    • Luana Janaína de Campos
      Luana Janaína de Campos
      Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska 68198, United States
      More by Luana Janaína de Campos
    • Nicholas Y. Palermo
      Nicholas Y. Palermo
      Computational Chemistry Core Facility, Vice Chancellor for Research Cores, University of Nebraska Medical Center, Omaha, Nebraska 68198, United States
      More by Nicholas Y. Palermo
    • Martin Conda-Sheridan*
      Martin Conda-Sheridan
      Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska 68198, United States
      *Email: [email protected]. Phone: +1-402-559-9361.
      More by Martin Conda-Sheridan
      Orcidhttps://orcid.org/0000-0002-3568-2545
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    The Journal of Physical Chemistry B

    Cite this: J. Phys. Chem. B 2021, 125, 24, 6572–6586
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    https://doi.org/10.1021/acs.jpcb.1c02398
    Published June 11, 2021
    Copyright © 2021 American Chemical Society
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    Abstract

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    Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has evolved into a pandemic of unprecedented scale. This coronavirus enters cells by the interaction of the receptor binding domain (RBD) with the human angiotensin-converting enzyme 2 receptor (hACE2). In this study, we employed a rational structure-based design to propose 22-mer stapled peptides using the structure of the hACE2 α1 helix as a template. These peptides were designed to retain the α-helical character of the natural structure, to enhance binding affinity, and to display a better solubility profile compared to other designed peptides available in the literature. We employed different docking strategies (PATCHDOCK and ZDOCK) followed by a double-step refinement process (FIBERDOCK) to rank our peptides, followed by stability analysis/evaluation of the interaction profile of the best docking predictions using a 500 ns molecular dynamics (MD) simulation, and a further binding affinity analysis by molecular mechanics with generalized Born and surface area (MM/GBSA) method. Our most promising stapled peptides presented a stable profile and could retain important interactions with the RBD in the presence of the E484K RBD mutation. We predict that these peptides can bind to the viral RBD with similar potency to the control NYBSP-4 (a 30-mer experimentally proven peptide inhibitor). Furthermore, our study provides valuable information for the rational design of double-stapled peptide as inhibitors of SARS-CoV-2 infection.

    Copyright © 2021 American Chemical Society

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    Supporting Information

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    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.jpcb.1c02398.

    • Two-dimensional structures of the designed stapled peptides; schematic representation of SARS-CoV-2 RBD from the spike protein and hACE2 receptor; 22-mer hACE2 from α1 helix crystallized structure overlaid with the docking prediction of the same structure for PATCHDOCK and ZDOCK servers; RMSD fluctuations of the spike protein and modification 4, modification 14, modification 13, original 3, modification 10, modification 9, and modification 3; RMSD fluctuations of the E484K-mutated spike protein and modification 11 and modification 15; RMSD values (Å) for the studied complexes; main interactions (>10% of persistence) between SARS-CoV-2 and the controls; and predicted free energies of binding (ΔGbind) from the MM-GBSA analysis (PDF)

    • MD simulation trajectory of modification 15 (Movie S1) (MP4)

    • MD simulation trajectory of modification hACE2 (Movie S2) (MP4)

    • MD simulation trajectory of modification 3 (Movie S3) (MP4)

    • MD simulation trajectory of modification NYBSP-4 (Movie S4) (MP4)

    • MD simulation trajectory of modification 11 (Movie S5) (MP4)

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    This article is cited by 15 publications.

    1. Nikhil Maroli. Riding the Wave: Unveiling the Conformational Waves from RBD of SARS-CoV-2 Spike Protein to ACE2. The Journal of Physical Chemistry B 2023, 127 (40) , 8525-8536. https://doi.org/10.1021/acs.jpcb.3c04366
    2. Aditya K. Padhi, Soumya Lipsa Rath, Timir Tripathi. Accelerating COVID-19 Research Using Molecular Dynamics Simulation. The Journal of Physical Chemistry B 2021, 125 (32) , 9078-9091. https://doi.org/10.1021/acs.jpcb.1c04556
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    6. Qian Zhang, Ziyang Wang, Xiaohan Mei, Quan Chen, Chunqiu Zhang. Stapled peptides: targeting protein-protein interactions in drug development. Exploration of Drug Science 2024, , 154-189. https://doi.org/10.37349/eds.2024.00041
    7. Giacomo Parisi, Roberta Piacentini, Alessio Incocciati, Alessandra Bonamore, Alberto Macone, Jakob Rupert, Elsa Zacco, Mattia Miotto, Edoardo Milanetti, Gian Gaetano Tartaglia, Giancarlo Ruocco, Alberto Boffi, Lorenzo Di Rienzo. Design of protein-binding peptides with controlled binding affinity: the case of SARS-CoV-2 receptor binding domain and angiotensin-converting enzyme 2 derived peptides. Frontiers in Molecular Biosciences 2024, 10 https://doi.org/10.3389/fmolb.2023.1332359
    8. Aganze Gloire-Aimé Mushebenge, Samuel Chima Ugbaja, Nonkululeko Avril Mbatha, Rene B. Khan, Hezekiel M. Kumalo. Assessing the Potential Contribution of In Silico Studies in Discovering Drug Candidates That Interact with Various SARS-CoV-2 Receptors. International Journal of Molecular Sciences 2023, 24 (21) , 15518. https://doi.org/10.3390/ijms242115518
    9. Ana Laura Pereira Lourenço, Thuanny Borba Rios, Állan Pires da Silva, Octávio Luiz Franco, Marcelo Henrique Soller Ramada. Peptide Stapling Applied to Antimicrobial Peptides. Antibiotics 2023, 12 (9) , 1400. https://doi.org/10.3390/antibiotics12091400
    10. Waseem Ahmad Ansari, Safia Obaidur Rab, Mohammad Saquib, Aqib Sarfraz, Mohd Kamil Hussain, Mohd Sayeed Akhtar, Irfan Ahmad, Mohammad Faheem Khan. Pentafuhalol-B, a Phlorotannin from Brown Algae, Strongly Inhibits the PLK-1 Overexpression in Cancer Cells as Revealed by Computational Analysis. Molecules 2023, 28 (15) , 5853. https://doi.org/10.3390/molecules28155853
    11. Roxana-Maria Amărandi, Maria-Cristina Al-Matarneh, Lăcrămioara Popovici, Catalina Ionica Ciobanu, Andrei Neamțu, Ionel I. Mangalagiu, Ramona Danac. Exploring Pyrrolo-Fused Heterocycles as Promising Anticancer Agents: An Integrated Synthetic, Biological, and Computational Approach. Pharmaceuticals 2023, 16 (6) , 865. https://doi.org/10.3390/ph16060865
    12. Abd. Kakhar Umar, James H. Zothantluanga, Jittima Amie Luckanagul, Patanachai Limpikirati, Sriwidodo Sriwidodo. Structure-based computational screening of 470 natural quercetin derivatives for identification of SARS-CoV-2 M pro inhibitor. PeerJ 2023, 11 , e14915. https://doi.org/10.7717/peerj.14915
    13. Abd. Kakhar Umar, James H. Zothantluanga, Keerthic Aswin, Saipul Maulana, Muhammad Sulaiman Zubair, H. Lalhlenmawia, Mithun Rudrapal, Dipak Chetia. Antiviral phytocompounds “ellagic acid” and “(+)-sesamin” of Bridelia retusa identified as potential inhibitors of SARS-CoV-2 3CL pro using extensive molecular docking, molecular dynamics simulation studies, binding free energy calculations, and bioactivity prediction. Structural Chemistry 2022, 33 (5) , 1445-1465. https://doi.org/10.1007/s11224-022-01959-3
    14. Asha Rani Choudhury, Atanu Maity, Sayantani Chakraborty, Rajarshi Chakrabarti. Computational design of stapled peptide inhibitor against SARS‐CoV ‐2 receptor binding domain. Peptide Science 2022, 114 (5) https://doi.org/10.1002/pep2.24267
    15. Susan Tzotzos. Stapled peptides as potential inhibitors of SARS‐CoV‐2 binding to the hACE2 receptor. Journal of Peptide Science 2022, 28 (9) https://doi.org/10.1002/psc.3409
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    The Journal of Physical Chemistry B

    Cite this: J. Phys. Chem. B 2021, 125, 24, 6572–6586
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acs.jpcb.1c02398
    Published June 11, 2021
    Copyright © 2021 American Chemical Society
    Request reuse permissions

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