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Macrolides May Prevent Severe Acute Respiratory Syndrome Coronavirus 2 Entry into Cells: A Quantitative Structure Activity Relationship Study and Experimental Validation

  • Jorge Galvez*
    Jorge Galvez
    Molecular Topology and Drug Design Unit, Department of Physical Chemistry, Universitat de Valencia, Burjassot 46100, Spain
    *Email: jorge[email protected]. Tel.: +34-963544891.
    More by Jorge Galvez
    Orcidhttp://orcid.org/0000-0003-0928-8437
    • , 
  • Riccardo Zanni
    Riccardo Zanni
    Molecular Topology and Drug Design Unit, Department of Physical Chemistry, Universitat de Valencia, Burjassot 46100, Spain
    More by Riccardo Zanni
    Orcidhttp://orcid.org/0000-0002-3388-3730
    • , 
  • Maria Galvez-Llompart
    Maria Galvez-Llompart
    Molecular Topology and Drug Design Unit, Department of Physical Chemistry, Universitat de Valencia, Burjassot 46100, Spain
    Instituto de Tecnología Química, UPV-CSIC, Universidad Politícnica de Valencia, Valencia 46022, Spain
    More by Maria Galvez-Llompart
    Orcidhttp://orcid.org/0000-0002-0718-4143
    • , and 
  • Jose Maria Benlloch
    Jose Maria Benlloch
    Instituto de Instrumentación para Imagen Molecular, Centro Mixto CSIC—Universitat Politècnica de València, Valencia 46022, Spain
    More by Jose Maria Benlloch
Cite this: J. Chem. Inf. Model. 2021, 61, 4, 2016–2025
Publication Date (Web):March 18, 2021
https://doi.org/10.1021/acs.jcim.0c01394
Copyright © 2021 American Chemical Society
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Abstract

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The global pandemic caused by the emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is threatening the health and economic systems worldwide. Despite the enormous efforts of scientists and clinicians around the world, there is still no drug or vaccine available worldwide for the treatment and prevention of the infection. A rapid strategy for the identification of new treatments is based on repurposing existing clinically approved drugs that show antiviral activity against SARS-CoV-2 infection. In this study, after developing a quantitative structure activity relationship analysis based on molecular topology, several macrolide antibiotics are identified as promising SARS-CoV-2 spike protein inhibitors. To confirm the in silico results, the best candidates were tested against two human coronaviruses (i.e., 229E-GFP and SARS-CoV-2) in cell culture. Time-of-addition experiments and a surrogate model of viral cell entry were used to identify the steps in the virus life cycle inhibited by the compounds. Infection experiments demonstrated that azithromycin, clarithromycin, and lexithromycin reduce the intracellular accumulation of viral RNA and virus spread as well as prevent virus-induced cell death, by inhibiting the SARS-CoV-2 entry into cells. Even though the three macrolide antibiotics display a narrow antiviral activity window against SARS-CoV-2, it may be of interest to further investigate their effect on the viral spike protein and their potential in combination therapies for the coronavirus disease 19 early stage of infection.

  Note

This article is made available via the ACS COVID-19 subset for unrestricted RESEARCH re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.

1. Introduction

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The world is being threatened by the emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is responsible for the current global pandemic. This virus was recently discovered as the etiological agent responsible for the coronavirus disease 19 (COVID-19), (1) and in few months, it has spread over the entire world causing more than 38.000.000 confirmed cases and 1.089.000 deaths, as of October 15, 2020 (https://covid19.who.int). COVID-19 is characterized by nonspecific symptoms that include fever, malaise, and pneumonia, which can eventually deteriorate into more severe respiratory failure, sepsis, and death. SARS-CoV-2 is a betacoronavirus belonging to the family Coronaviridae, order Nidovirales. It is an enveloped virus with a positive-sense single-stranded RNA genome. SARS-CoV-2 enters the cell through the interaction of the viral surface glycoprotein, the spike (S) protein, with its cellular receptor, the angiotensin-converting enzyme 2 (ACE2) protein. (2) The transmembrane serine protease 2 (TMPRSS2) has been proposed to be responsible for the cleavage of S protein, facilitating cell entry. (2) Once inside the cell, the viral genome is translated into two polyproteins that are processed by the main protease 3CLpro and the papain-like protease (PLpro) producing nonstructural proteins (nsps). The viral genome is also used for replication and transcription, processes that are mediated by the viral RNA-dependent RNA polymerase (nsp12). (3) Until now, remdesivir is the only antiviral compound approved by the Food and Drug Administration for the treatment of SARS-CoV-2 infection because it has been shown to reduce the hospitalization time in severe cases of COVID-19. (4) However, its efficacy as an antiviral agent against SARS-CoV-2 infection needs to be clearly demonstrated. Moreover, during the second and third waves of infection, even with the first doses of vaccines available, the severity of new strains of SARS-CoV-2 keeps worsening the gravity of the situation. The lack of a widely approved treatment has directed the efforts of many researchers toward the development of new compounds or repurposing existing ones. Broadly, current strategies are focused on compounds that block: (i) viral entry by affecting S-ACE2 interaction, (ii) viral nucleic acid synthesis, (iii) viral protease activity, and (iv) cytokine storm production. Many different clinically approved drugs are being currently tested as potential antivirals in SARS-CoV-2 infected patients around the world, including lopinavir, ritonavir, tocilizumab, and azithromycin, among many others (https://ClinicalTrials.gov). Azithromycin and other macrolides have been suggested because of their alleged role in preventing bacterial superinfection and their immunomodulatory and anti-inflammatory effects. (5−9) They also have demonstrated certain efficacy in reducing the severity of respiratory infections in different clinical studies. (10−13) Macrolides have been empirically prescribed for patients with pneumonia caused by novel coronaviruses such as SARS and MERS (14−16) and, more recently, SARS-CoV-2, with azithromycin attracting special attention after the release of a nonrandomized study, with methodological limitations, and an observational study, which claims that the combination of hydroxychloroquine and azithromycin achieved a higher level of SARS-CoV-2 clearance in respiratory secretions. (17,18) In the study, authors assessed the clinical outcomes of 20 patients with suspected COVID-19 who were treated with hydroxychloroquine (200 mg TDS for 10 days). Of these 20 patients, six additionally received azithromycin to prevent bacterial superinfection. On Day 6, 100% of patients in the combined hydroxychloroquine and azithromycin group were virologically cured; this was significantly higher than in patients receiving hydroxychloroquine alone (57.1%) (p < 0.001). However, the efficacy of macrolides in treating SARS-CoV-2 infection based on clinical study results seems to be controversial, especially when it comes to mild and severe situations. Several authors reported results in which no significant improvement has been observed when macrolides have been administered to COVID-19 patients; (19,20) for example, in the study of Furtado et al., (21) of 397 patients with COVID-19 confirmed, 214 were assigned to the azithromycin group and 183 to the control group with no significant improvements. It has to be reported, as stated by authors, that the entry criterion required for patients was to be on oxygen of more than 4 L/min, resulting in inclusion of a very high-risk population, with almost half of the patients on mechanical ventilation and about a quarter in shock at the baseline. With all that said, authors’ main objective here is to provide new, significant insights into the potential role of macrolides in treating COVID-19 infections during the early stages. To be precise, the present quantitative structure activity relationship (QSAR) study provides new in silico and in vitro data related to azithromycin and other macrolides’ capability in reducing or even impeding the entrance of the virus into hosting cells by targeting the spike receptor or by decreasing the intracellular accumulation of viral RNA and virus spread. In this report, an in silico study based on the construction of a molecular topology QSAR strategy (22) is developed, which led to the identification of a number of clinically approved macrolide antibiotics as potential agents against SARS-CoV-2 infection. The antiviral effect of macrolides is then tested in cell culture, and results suggest that azithromycin, clarithromycin, and lexithromycin display antiviral activity against SARS-CoV-2 by impeding viral entry.

2. Results and Discussion

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2.1. QSAR Predictive Models Based on Molecular Topology for SARS-CoV-2 Inhibitory Activity

The first predictive model, based on discriminant analysis (DF1 function), recognizes compounds with SARS-CoV-2 inhibitory activity. The resulting equation is:(1)
where N = 103, Wilks’ lambda = 0.760, F = 32.005, and p < 0.00001
SPI: Topological superpendentic index.
In Table S1, the value of the descriptors for the compounds composing the training set is illustrated, as well as the classification and the probability of being classified as active by the model.
Table 1 reports the classification matrix obtained for DF1, focused on the prediction of antiviral activity against SARS-CoV-2. As can be seen, the model shows strong sensitivity and specificity. 90% of the active compounds and 87% of the inactive compounds have been correctly classified by the model, thus yielding an average rate of correct classification of 90% with a probability of 10% of misclassification of an inactive compound as a potential SARS-CoV-2 antiviral compound.
Table 1. Classification Matrix from Model 1
 percent of correct classificationcompounds classified as activecompounds classified as inactive
training set
active group92111
inactive group871279
total902380
As for the index composing the discriminant equation, the superpendentic index (SPI) is a topological descriptor calculated from the pendent matrix, a submatrix of the distance matrix. This descriptor takes into account the branching of a molecule. In our model, it contributes positively to the discriminant function (DF), so it is expected that molecules with greater branching are related to the ability of exerting an antiviral effect against SARS-CoV-2. In Figure 1, it can be seen how the compounds with an antiviral effect against SARS-CoV-2 in general present a greater branching level in their molecular structure with respect to the inactive compounds. In fact, when analyzing the values of SPI for the training set (see Table S1), the compounds with SPI values >20 are classified by DF1 as antivirals, while those with values <20 are classified as inactives. The only exception is for arbidol, a compound that presents a lower degree of branching than the rest of the actives (Table S1).

Figure 1

Figure 1. Example of SPI values for active and inactive molecules in the DF1 training set.

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To assess the robustness of the discriminant model, DF1 was internally validated using the leave-some-out technique (25% of the training data has been used as a test set). Because we have a limited number of active compounds in the training set (n = 12), this technique is the best way to check the performance of the system, giving us information about model’s ability to predict potential unseen data. Results are reported in Table S2 (in the Supporting Information), and as it can be seen, an average value of correct classification for the test set of 98% is obtained. Once the model has been validated, it is possible to analyze its applicability range. The PDD or pharmacological distribution diagram (Figure 2) shows a greater expectancy of finding antiviral compounds against SARS-CoV-2 for values of the DF ≥ −0.5. Therefore, when searching for potential SARS-CoV-2 inhibitors, this criterion will be taken into account.

Figure 2

Figure 2. PDD for DF1. Filled bars for the active and empty bars for the inactive.

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The second predictive model (DF2) focuses on the identification of molecules with potential SARS-CoV-2 spike protein inhibitory activity. The resulting equation was:(2)
where N = 91, λ = 0.3866, F = 70.615, p < 0.00001, MATS1s is the Moran autocorrelation of lag 1 weighted by the I-state, andGATS3iis the Geary autocorrelation of lag 3 weighted by ionization potential.
In Table S3, the values of the descriptors for the different compounds of the training set as well as the classification and the probability of activity are shown.
As may be deduced from the DF2 classification matrix (Table 2), the model is capable of correctly classifying 100% of the active compounds and 96% of the inactive compounds, showing strong specificity and sensitivity.
Table 2. Classification Matrix from Model 2
 percent of correct classificationcompounds classified as activecompounds classified as inactive
training set
active group10080
inactive group96380
total981181
DF2 descriptors are MATS1s and GATS3i. The GATS3i descriptor or Geary autocorrelation of lag 3 weighted by the ionization potential index contributes positively to the equation, so that higher values would result in a greater probability of potential SARS-CoV-2 spike protein inhibition activity. In this specific case, GATS3 is weighted by the ionization potential; hence compounds with atoms at distance 3, presenting higher ionization potentials (niclosamide or aristolochic acid), adopt higher values of this descriptor (Figure 3), while compounds that do not present atoms at distance 3 (mercaptomethyl) present the lowest value of the training set. Compounds described as spike protein inhibitors have GATS3i values >1 (Table S3), although some inactive compounds with GATS3i values >1 are also found (aristolochic acid, cyano-quinocarmycin, dexecadotril, maridomycin propionate, plicamycin, and ramoplanin A2). It is to be noted that only two of them have been classified as active by the model and that plicamycin is indeed described as the spike protein inhibitor in the literature. (23)

Figure 3

Figure 3. Example of GATS3i values for active and inactive molecules of the DF2 training set.

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MATS1s, or Moran autocorrelation index of lag 1 weighted by the I-state, is a descriptor calculated by applying the Moran coefficient to a molecular graph using the intrinsic state(s) as the atomic property. In this case, it contributes negatively to the equation; therefore, in general terms, small values of this index will contribute to the inhibitory effect against virus’ spike protein (Table S3). Again, using the leave-some-out technique, approximately 25% of the data set is left out as a test set, while the remaining data are used to calculate the model values. The new results are analyzed, and as shown in the Supporting Information, Table S4, the model is capable of correctly classifying almost 100% of the compounds of the test group. Once the model has been validated, the PDD is analyzed, to establish the DF value interval of activity. As illustrated in Figure 4, spike SARS-CoV-2 protein inhibitors have a higher chance to be found for DF2 value >0.

Figure 4

Figure 4. PDD for SARS-CoV-2 spike protein inhibitors (filled bars) and inactive compounds (empty bars) obtained using DF2.

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2.2. Screening Macrolide Searching for Potential SARS-CoV-2 Inhibitors

Once the QSAR models were built and validated, the mathematical pattern for molecules exhibiting a general antiviral effect and/or spike SARS-CoV-2 protein inhibitory effect is analyzed. The objective is to determine if macrolides in clinical use share the same topological pattern. Table 3 shows the descriptors calculated for the macrolides under study, as well as the value of the DFs and the probability to be classified as active by both discriminant equations. As it can be seen, the macrolides present a mathematical pattern compatible with that presented by those molecules exhibiting antiviral activity against SARS-CoV-2 (DF1 > −0.5); therefore, DF1 would classify them as potential anti-SARS-CoV-2 agents.
Table 3. Prediction of Antiviral and Spike Protein Inhibitory Activity for Macrolides in Clinical Use
compoundSPIDF1P.AMATS1sGATS3iDF2P.A.
azithromycin44,3751410,997–0,164132712,2191000
clarithromycin44,26951210,997–0,137125783251000
erythromycin43,72550100,996–0,149126892741000
lexithromycin44,83652360,997–0,149128398341000
The same way as the antivirals, macrolides present a value of the SPI descriptor (DF1) > 20 (high degree of branching molecules); therefore, the model classifies them as potential anti-SARS-CoV-2 (Figure 5).

Figure 5

Figure 5. SPI descriptor values for all macrolides under study.

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Once their potential as anti-SARS-CoV-2 is determined, the authors studied whether macrolides could exert antiviral activity through the inhibition of the virus spike protein. To do this, the mathematical pattern exhibited by the spike protein inhibitors (DF2 > 0) is compared with the one of macrolides. Actually, by analyzing the value of the GATS3i descriptor for macrolides, it adopts a value greater than 1 in all cases, and this is in accordance with the discriminant model outcomes for the inhibitory activity against the spike protein of SARS-CoV-2 (DF2). In summary, according to the mathematical-topological models (DF1 and DF2), macrolides would simulate the antiviral effect through the inhibition of the SARS-CoV-2 spike protein.

2.3. Evaluation of Macrolides as Candidate Drugs against Human Coronavirus Infection

As a preliminary approach to confirm the antiviral potential of the aforementioned antibiotics against SARS-CoV-2, the effective concentration of the compounds capable of blocking infection by a human recombinant model coronavirus bearing a reporter gene (229E-GFP) was determined. Azithromycin, clarithromycin, and lexithromycin blocked viral infection in the absence of cytotoxicity at micromolar concentrations (Table 4). In this assay, clarithromycin showed a slightly lower potency than the other two active compounds.
Table 4. Antiviral Activity and Cytotoxicity Indexes of Selected Compounds in the 229E-GFP Infection System
compoundEC50 (μM)EC90 (μM)CC50 (μM)
azithromycin6.1 ± 2.418.8 ± 2.5> 50
clarithromycin17.3 ± 9.246.3 ± 4.8> 50
erythromycin> 50> 50> 50
lexithromycin3.0 ± 1.416.3 ± 6.0> 50
As stated in Table 4, all tested macrolides except erythromycin were active against 229E coronavirus. Hence, the inhibitory effect of clarithromycin, azithromycin, and lexithromycin against SARS-CoV-2 infection is tested to confirm their antiviral potential activity. Results show how azithromycin, clarithromycin, and lexithromycin inhibit viral infection in the absence of cytotoxicity at micromolar concentrations (Table 5). The same pattern of antiviral potency is reproduced in both assays against 229E coronavirus and SARS-CoV-2 where lexithromycin is depicted as the most potent one followed by azithromycin. In both assays, clarithromycin was the macrolide with lower antiviral activity.
Table 5. Antiviral Activity and Cytotoxicity Indexes of Selected Compounds in SARS-CoV-2
compoundEC50 (μM)CC50 (μM)
azithromycin52 ± 4.3400 ± 15.7
clarithromycin105 ± 8.6> 200
lexithromycin14 ± 2.1120 ± 10.4

2.4. Clarithromycin, Azithromycin, and Lexithromycin Interfere with SARS-CoV-2 Virus Infection

Given the antiviral activity in the 229E-GFP infection system and to evaluate the antiviral potential of the antibiotics in a bona fide SARS-CoV-2 infection model, we performed multiple cycle infection experiments (MOI 0.001) in the presence of a range of doses of the vehicle (DMSO) or the compounds that showed antiviral potential against 229E-GFP: azithromycin, clarithromycin, and lexithromycin. All three compounds protected target cells from SARS-CoV-2 infection-induced cell death, as shown in Figure 6A,B, indicating that these compounds are capable of interfering with virus infection sufficiently to protect the target cells from cell death. Using this assay, it was possible to calculate an effective concentration 50 as a surrogate indicator of the relative potency of the compounds. Azithromycin showed the lowest potency as it could only protect completely the cell monolayer at 200 μM (EC50 = 75 μM). Interestingly, clarithromycin and lexithromycin showed increasing potency, protecting around 100% of the cell population at 100 and 50 μM, respectively (EC50 = 60 and 25 μM, respectively).

Figure 6

Figure 6. Selected antibiotics protect from the cytopathic effect of SARS-CoV-2 infection. Vero-E6 cells were inoculated at MOI 0.001 with SARS-CoV-2 in the absence or presence of increasing doses of the compounds. (A and B) Seventy-two hours later, cells were fixed and stained with crystal violet, and the percentage of remaining biomass was estimated per well. (A) Image of a representative experiment showing protection from SARS-CoV-2 infection. (B) Quantitation of the data shown in A. Data are shown as the average and standard deviation of three biological replicates and are expressed as the relative protection in the presence of the compound as compared with the vehicle (DMSO). (C) Toxicity of compounds was determined by quantitation of crystal violet staining of uninfected Vero-E6 cells that were treated in parallel as described in panel A. Data are shown as the average and standard deviation (Mean; SD; n = 3).

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The cytotoxicity study reported in Figure 6C allows appreciating how lexithromycin, clarithromycin, and azithromycin do not exert a cytotoxic effect on viral cells when used at maximum concentrations of 50, 100, and 200 μM, respectively. Furthermore, the macrolide with a wider therapeutic window in terms of cytotoxicity seems to be azithromycin. Although this can be considered a simplification because no simple correlation between in vitro cytotoxicity and in vivo toxicity of specific drugs is possible, (24) indeed macrolides seem to have a relatively high margin of safety (high therapeutic index). (25)
As shown in Figure 7, azithromycin (100 μM), clarithromycin (100 μM), and lexithromycin (50 μM) reduced progeny virus production to undetectable levels, as determined by TCID50 (lower limit of detection (LoD) = 100 TCID50/ml), in the absence of cytotoxicity (Figure 6C). These results confirm that the protective effect of the compounds is associated with the antiviral activity of the compounds.

Figure 7

Figure 7. Selected antibiotics display antiviral activity against SARS-CoV-2 infection. Vero-E6 cells were inoculated at MOI 0.001 with SARS-CoV-2 in the presence of nontoxic concentrations of azithromycin (100 μM), clarithromycin (100 μM), or lexithromycin (50 μM). Forty-eight hours postinfection, supernatants were collected, and the infectivity titers were determined. Data are expressed as average and standard deviation of the TCID50 values per ml of supernatant obtained in control and compound-treated cells. The lower LoD of the assay is represented by the discontinued gray line. Note that virus was undetectable in compound-treated conditions, despite the fact that supernatants were diluted below the effective concentrations during the titration assay.

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Then, single-cycle infection experiments were performed to determine which of the steps in the virus life cycle are affected by the antibiotics. Treatment with all three compounds significantly reduced viral RNA accumulation in a dose-dependent manner, clarithromycin and lexithromycin being more potent than azithromycin (Figure 8, black bars). These results suggest that compounds inhibit early steps in the infection leading to the reduction of intracellular viral RNA. To explore this possibility, a time-of-addition experiment was performed by treating the cells 2 h after virus inoculation (white bars). As shown in Figure 9, the antiviral effect was markedly reduced when compounds were added after the virus had entered the cells, suggesting that they might interfere with virus cell entry.

Figure 8

Figure 8. Selected antibiotics reduce intracellular SARS-CoV-2 RNA accumulation. Vero-E6 cells were inoculated at MOI 5 with SARS-CoV-2 in the presence or absence of the indicated compound concentrations. (A) Diagram explaining the experimental setup used in the experiment. Cells were treated with the compounds either at the time of virus inoculation (black bar) or 2 h thereafter (white bar), and compounds were maintained until the end of the experiment. At 6 h postinfection, cell lysates were prepared, and the RNA content was analyzed as described in the Materials and Methods section. (B) Relative intracellular SARS-CoV-2 RNA quantitation in control and compound-treated samples. Data are expressed as the average and standard deviation of biological triplicates. Note that the antiviral effect of compounds is greatly reduced when they are added after virus entry has occurred (white bars) compared to when they are added together with the virus (black bars).

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Figure 9

Figure 9. Selected antibiotics inhibit SARS-CoV-2 entry into target cells. Vero-E6 cell monolayers were inoculated with retroviral vectors pseudotyped with SARS-CoV-2 spike protein (SARS2pp) or VSV envelope glycoprotein (VSVpp) in the absence or presence of increasing doses of the compounds (i.e., 50 and 100 μM for azithromycin and clarithromycin and 12.5 and 25 μM for lexithromycin). Forty-eight hours postinoculation, luciferase activity was determined in whole-cell lysates. Data are expressed as relative luciferase activity values obtained in control and compound-treated cells. Data are shown as the average and standard deviation of three biological replicates.

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2.5. Clarithromycin, Azithromycin, and Lexithromycin Inhibit SARS-CoV-2 Spike Protein-Mediated Viral Entry

To determine the impact of the antibiotics on viral entry, we assessed the ability of retroviral vectors pseudotyped with SARS2 S protein to enter Vero-E6 target cells in the presence of the compounds. Virus infection efficiency results suggest that all three antibiotics significantly inhibit S-mediated viral entry (Figure 9). These compounds display the expected relative effectiveness observed in the SARS-CoV-2 infection experiments lexithromycin being the most potent compound (EC50 ≅ 18 μM) and clarithromycin and azithromycin displaying comparable, lower potency (EC50 ≅ 30 μM). In parallel, entry of retroviral vectors pseudotyped with VSV G protein (VSVpp) was not inhibited by any of the tested compounds at the highest, nontoxic concentrations, suggesting that the compounds do not interfere with reporter gene expression and that they selectively inhibit S-mediated virus entry.

3. Conclusions

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A QSAR pattern recognition analysis employing topological and topo-chemical descriptors has been performed on antiviral and spike protein inhibitor agents against SARS-CoV-2. After the construction and validation of two discriminant models (DF1 and DF2), macrolides have been searched. From the computational study, some macrolides show a mathematical pattern compatible with that of antiviral and spike protein inhibitors, giving insights into the capability of these antibiotics in exerting such activity. Azithromycin, clarithromycin, erythromycin, and lexithromycin have been identified as the most promising candidates. Further in vitro results indicate that azithromycin, clarithromycin, and lexithromycin display antiviral behavior against human alpha- and beta-coronaviruses in cell culture infection models. According to the present experimental results, all three antibiotics seemed to be capable of reducing the SARS-CoV-2 entry into cells, suggesting that they interfere with early aspects of virus infection. Clarithromycin, azithromycin, and lexithromycin inhibit SARS-CoV-2 spike protein-mediated viral entry; however, other mechanisms for preventing viral entry cannot be excluded (considering that 229E and SARS-CoV-2 entry is mediated by different cellular receptors). This outcome is not totally unexpected as azithromycin and clarithromycin have been shown to effectively interfere with cellular endocytosis (26,27) and with influenza virus infection. (13) Clarithromycin (28) and azithromycin were found to be active at lower doses against HCV infection in cell culture (screen in ref. (29)). Thus, these compounds are not specific antivirals against SARS-CoV-2 infection. The efficacy of clarithromycin as an antiviral drug has also been tested in nonhuman primates challenged with influenza viruses of different pathogenicity. (30) In that study, clarithromycin showed a modest therapeutic antiviral effect and reduction of overall pathogenesis, although it was suggested that it might contribute to amelioration of the course of the disease for its ability to reduce virus-induced inflammation. (8) In fact, similar to other lysosomotropic drugs (such as hydroxychloroquine and related compounds), macrolides have been previously considered in the treatment of respiratory viral infections not only for their antiviral potential, but also for their immunomodulatory role and potential reduction of virus-induced inflammation. (31) In summary, based on the present results, clarithromycin and lexithromycin seem to exert in cell culture a higher antiviral potency against SARS-CoV-2 than azithromycin, which is currently under clinical evaluation by several agencies as a component of therapies aimed at reducing COVID-19 severity. Despite the relatively small therapeutic window observed in cell culture, these compounds are approved for clinical use at higher dosages. Furthermore, high bioavailability at the upper and lower respiratory tract for these molecules is described. (32) Considering the present in silico and in vitro results, but also considering the controversial outcomes of several clinical studies showing no significant effects in reducing severe infection from SARS-CoV-2, authors consider of interest to further investigate if macrolides may be capable of preventing or reducing the gravity of COVID-19 infection during the early stages by inhibiting the spike receptor, as previously suggested for other viral respiratory infections. (8,31)In vitro results point out that three macrolide antibiotics such as azithromycin, clarithromycin, and lexithromycin exhibit antiviral activity against two distinct human coronaviruses (i.e., SARS-CoV-2 and 229E) by inhibiting entry into target cells. Our results suggest that these clinically approved antibiotics may be capable of reducing COVID-19 early infection, if administered early on after symptoms. Furthermore, and no less important, the present in silico strategy can be used to search new, better macrolide derivatives with improved efficacy against the SARS-CoV-2 spike receptor and to optimize the potency of the macrolides examined here.

4. Materials and Methods

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4.1. Compounds

Clinically approved compounds erythromycin (HY-B02020), clarithromycin (HY-17508), cefuroxime sodium (HY-B1256), and lexithromycin (HY-105932) were purchased from MedChemExpress (USA), while azithromycin dehydrate (PZ0007) was obtained from Merck (USA). Stock solutions were prepared in dimethyl sulfoxide (DMSO) at a final concentration of 10 mM. DMSO was used as the vehicle control in all experiments.

4.2. In Silico Predictions Based on Molecular Topology

4.2.1. Compound Analysis and Molecular Descriptors

For the construction of the first topological model, a general database of SARS-CoV-2 inhibitors is created collecting information from the literature. (32−34) The group of inactive compounds was created collecting molecules from the comprehensive medicinal chemistry database (CMC), (35) searching the literature for already described activity on SARS-CoV-2 for every molecule and taking into account different chemical and structural features to reach a coherent balance on chemical diversity between the groups (for example, to contain similar values of molecular mass, number of heteroatoms, functional groups, alicyclic or aromatic rings, etc.). The same procedure was followed for the second QSAR equation; however this time, the training set data for the active were retrieved from references. (2,36−40) After a comprehensive analysis of the data set, all the molecules have been represented as a set of descriptors such as constitutional and topological descriptors. The indices were calculated with alvaDesc software version, (41) and their values for the selected equations for every compound included in this study (training set, external test set, and virtual screening set) are shown in the Supporting Information.

4.2.2. Modeling Techniques and Validation

Linear discriminant analysis (LDA) allows calculating a DF, which best separates two categories or objects. When developing the QSAR models presented here, the most significant descriptors, those allowing the best separation between two categories of objects, are selected. (42) When selecting the descriptors, the Furnival–Wilson algorithm (43,44) was followed, and the Fisher Snedecor parameter (F), which establishes the relevance of candidate variables, was used. Variables were chosen in a stepwise procedure according to the F value (to be exactly, an F value >1). Next, the descriptor or combination of descriptors that better explains the difference between the two groups is selected. Discriminant capability was assessed as the percentage of correct classifications in each set of compounds. Its classification criterion is based on the minimum Mahalanobis distance (the distance of each case to the mean of all cases in a category), and the quality of discrimination was evaluated using Wilks’ lambda (λ) parameter, which is related to the multivariate analysis of variance that tests the equality of group means for the variable in the discriminant model. The smaller is the Wilks’ parameter value, the smaller is the overlap between active and inactive (λ = 0 would mean a perfect separation between the groups). Validation of the DFs was performed using internal (y-randomization) validation techniques. To be exact, the leave-some-out method (45) consists of taking out a percentage of the data set and assigning it as a test group. The predictive model is calculated with the rest of the data set, and the leave-some-out group is analyzed. The percentage of correct classification for the test group gives insights about the reliability of the model. The software used for LDA was Statistica 9.0. (46)

4.3. Potency and Cytotoxicity Indexes Using a 229E-GFP Infection Assay

Huh7-Lunet#3 cells (kindly provided by Dr. Thommas Pietschmann; Twincore-Hannover) were maintained subconfluent in complete media [(DMEM supplemented with 10 mM HEPES, 1X nonessential amino acids (Gibco), 100 U/ mL penicillin–streptomycin (Gibco), and 10% fetal bovine serum (FBS; heat-inactivated at 56 °C for 30 min)].
Huh7-Lunet#3 cells were seeded onto 96-well plates (1 × 104 cells/well). The day after, compound stock solutions (10 mM in DMSO) were diluted into complete cell culture media to achieve a final concentration of 100 μM. The 100 μM solution was serially diluted 3-fold to achieve decreasing compound concentrations. On the other hand, 229E-GFP virus stock (47) (kindly provided by Dr. Volker Thiel; University of Bern) was diluted in complete media to achieve a final concentration of 3 × 103 focus forming units (FFU)/ml. One hundred microliters (100 μL) of the virus dilution were mixed 1:1 with 100 μL of the compound dilutions to achieve final compound concentrations in a range from 50 μM to 22 nM and 150 infectious units (FFU) per well in a 96 well plate. One hundred μl of the mixture was applied onto the Huh7-Lunet#3 cell monolayer in biological replicates, and cells were cultured for 72 h at 33 °C in a 5% CO2 incubator. Cells were fixed in a 4% formaldehyde solution in PBS for 10 min at room temperature and washed twice with PBS, and individual well fluorescence was measured in a SpectraMax iD3 fluorescence plate reader (Molecular Devices). Background subtraction was performed using noninfected wells, and the signal was normalized to the average fluorescence found in vehicle (DMSO)-treated virus-infected wells. Relative infection efficiency was plotted versus compound concentration to determine the EC50 and EC90 (effective concentration) values. Once infection efficiency had been determined, plates were stained with a 0.1% crystal violet solution in water–methanol for 30–60 min. Then, plates were extensively washed with water and dried before 1% SDS solution in water was added to solubilize crystal violet. Absorbance was measured at 570 nm, and background was subtracted from blank wells. Relative well biomass was estimated by calculating the absorbance in each well relative to the average observed in infected cells treated with DMSO. Relative biomass was plotted versus compound concentration to determine the cytotoxic concentration (CC50) values.

4.4. SARS-CoV-2 Infection Assays

All high and low multiplicity of infection (MOI) experiments were performed by inoculating Vero-E6 cells seeded onto 96-well plates (2.5 × 104 cells/well) with the SARS-CoV-2 strain NL/2020 (kindly provided by Dr. R. Molenkamp, Erasmus University Medical Center Rotterdam). Cultures were maintained at 37 °C in a 5% CO2 incubator for different lengths of time as indicated in each experiment. Compounds were diluted from 10 mM stock solutions in complete media containing 2% FBS to achieve the indicated final concentrations.

4.4.1. Potency, Cytotoxicity, and Cell Monolayer Protection Assays

Vero-E6 cell monolayers were inoculated at MOI 0.001 in the presence of a wide range of compound concentrations (from 200 to 3.125 μM) in triplicate wells. Seventy-two hours later, the cells were fixed and stained using crystal violet, as described above. Stained cells were dissolved in 1% SDS in water, and absorbance at 570 nm was used to evaluate the biomass in each well. Uninfected wells and wells infected in the presence of the vehicle (DMSO) were used as references for 100 and 0% protection.

4.4.2. Extracellular Progeny Virus Determination

Vero-E6 cell monolayers were inoculated at MOI 0.001 in the presence of the indicated compound concentrations. Progeny virus accumulation, present in the supernatants, was determined at 48 h postinfection by TCID50 determination using the Reed and Muench method. (48)

4.4.3. Intracellular Viral RNA Quantitation

Vero-E6 cell monolayers were inoculated at MOI 5 in the presence of the indicated compound concentrations. Six hours later, cell lysates were prepared using Trizol reagent (Thermo Scientific). Viral RNA content was determined by RT-qPCR using previously validated sets of primers and probes specific for the detection of the SARS-CoV-2 E gene (49) and the cellular β-actin gene, (50) for normalization purposes. The δCt method was used for relative quantitation of the intracellular viral RNA accumulation in compound-treated cells compared to the levels in infected cells treated with DMSO, set as 100%. Time-of-addition experiments were performed by inoculating Vero-E6 cells with SARS-CoV-2 at MOI 5 in the absence of compounds. Two hours later, virus inoculum was discarded, cells were washed with PBS, and they were incubated in the presence of the indicated compound concentrations for 4 h. Then viral RNA was extracted and analyzed as described above.

4.5. SARS-CoV-2 Spike Protein-Pseudotyped Retroviral Vectors

Retroviral particle production pseudotyped with different viral envelopes has previously been described. (51) Packaging plasmids and vesicular stomatitis virus (VSV) G protein-expressing plasmid were kindly provided by Dr. F. L. Cosset (INSERM, Lyon). SARS-CoV-2 S-expressing plasmid was obtained from Jose María Casanovas and Juan García Arriaza (CNB-CSIC). Particles devoid of envelope glycoproteins were produced in parallel as controls.
For SARS-CoV-2 S protein-pseudotyped particle (SARS2pp) entry experiments, Vero-E6 cells (104 cells/well) were seeded onto 96-well plates the day before. Compounds were diluted in complete media [(DMEM supplemented with 10 mM HEPES, 1× nonessential amino acids (Gibco), 100 U/mL penicillin–streptomycin (Gibco), and 10% FBS (heat-inactivated at 56 °C for 30 min)] to achieve a 2× concentration. Fifty microliters (50 μL) of the SARS2pp or VSVpp retrovirus dilutions were mixed 1:1 with 50 μL of the 2x compound dilutions to achieve the desired final compound concentrations, as indicated in Figure 9. One hundred μl of the mixture was applied onto the Vero E6 cell monolayer in biological triplicates, and cells were cultured at 37 °C in a 5% CO2 incubator. Forty-eight hours postinoculation, cells were lysed for luciferase activity determination using a Luciferase Assay System (Promega) and a luminometer. Relative infection values were determined by normalizing the data to the average relative light units detected in the vehicle control cells.

4.6. Statistical Analysis

GraphPad Prism v.5.0a software was used to perform all statistical analyses. All the results were displayed in the graphs as the mean ± standard deviation. The mean differences between multiple groups were analyzed by one-way analysis of variance followed by Dunnett’s multiple comparison test. The statistical significance was set as: ns (not significant) P > 0.05; * P < 0.05; ** P < 0.01; and *** P < 0.001.

Supporting Information

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The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.jcim.0c01394.

  • Descriptor values, classification of compounds, and probability of activity for the training set of models 1 and 2 (Tables S1 and S3) and the leave-some-out validation test for DF1–2 (Tables S2 and S4) (PDF)

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Author Information

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  • Corresponding Author
  • Authors
    • Riccardo Zanni - Molecular Topology and Drug Design Unit, Department of Physical Chemistry, Universitat de Valencia, Burjassot 46100, Spain;  Orcidhttp://orcid.org/0000-0002-3388-3730
    • Maria Galvez-Llompart - Molecular Topology and Drug Design Unit, Department of Physical Chemistry, Universitat de Valencia, Burjassot 46100, Spain;  Instituto de Tecnología Química, UPV-CSIC, Universidad Politícnica de Valencia, Valencia 46022, Spain;  Orcidhttp://orcid.org/0000-0002-0718-4143
    • Jose Maria Benlloch - Instituto de Instrumentación para Imagen Molecular, Centro Mixto CSIC—Universitat Politècnica de València, Valencia 46022, Spain
  • Funding

    This project has been funded in part by the ERC Advanced Grant 695536 (4D-PET). This research was funded by the Spanish Ministry of Science and Innovation, grant number PIE-RD-COVID-19 ref. E202020E079 to the National Biotechnology Center (CNB-CSIC). This publication was supported by the European Virus Archive GLOBAL (EVA-GLOBAL) project that has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement No 871029.

  • Notes
    The authors declare no competing financial interest.

Acknowledgments

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We would like to thank P. Gastaminza and U. Garaigorta (Molecular and Cellular Biology Department, Centro Nacional de Biotecnología (CNB), Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain) for obtaining all in vitro results presented in this manuscript. J. Galvez acknowledges support from the MINECO (Spanish Ministry of Economy, Industry, and Competivity) via Project: “Rational Design Of New Phytoprotection Tools” (PID2019-107464RB-C22). We are grateful to the following investigators for sharing valuable reagents: Dr. T. Pietschmann (Twincore, Hannover, Germany) for the Huh7-Lunet#3 cell line; Dr. V. Thiel (University of Bern, Bern, Switzerland) for the 299E-GFP virus; Dr. R. Molenkamp (Erasmus University Medical Center, Rotterdam, Netherlands; participant of the EVA-GLOBAL project) for the SARS-CoV-2 strain NL/2020 virus; Dr. F.L. Closset (Inserm, Lyon, France) for the retrovirus packing plasmid system and the VSV G protein-expressing plasmid; and Drs. J. M. Casanovas and J. García-Arriaza (CNB-CSIC, Madrid, Spain) for the SARS-CoV-2 S-expressing plasmid.

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    Tahan, F.; Ozcan, A.; Koc, N.
    European Respiratory Journal (2007), 29 (1), 91-97CODEN: ERJOEI; ISSN:0903-1936. (European Respiratory Society)
    Respiratory syncytial virus (RSV) bronchiolitis is the most common lower respiratory tract infection in infancy. To date, there is no effective therapy for RSV bronchiolitis. In order to investigate the efficacy of clarithromycin in the treatment of RSV bronchiolitis, the present authors conducted a randomized, double-blind, placebo-controlled trial comparing clarithromycin with placebo in 21 infants with a diagnosis of RSV bronchiolitis. The infants were randomized to receive clarithromycin or placebo daily for 3 wk. Levels of interleukin (IL)-4, IL-8, eotaxin, and interferon-γ were detd. in plasma, before and after treatment, using ELISA. Six months after treatment, parents were surveyed as to whether their child had experienced wheezing within the previous 6 mo. Treatment with clarithromycin was assocd. with a statistically significant redn. in the length of hospital stay, the duration of need for supplemental oxygen and the need for β2-agonist treatment. There were significant decreases in plasma IL-4, IL-8 and eotaxin levels after 3 wk of treatment with clarithromycin. Readmission to the hospital within 6 mo after discharge was significantly lower in the clarithromycin group. In conclusion, clarithromycin has statistically significant effects on the clin. and lab. findings in respiratory syncytial virus bronchiolitis. Therefore, clarithromycin treatment may be helpful in reducing the short-term effects of respiratory syncytial virus bronchiolitis.
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  11. 11
    Suzuki, T.; Yamaya, M.; Sekizawa, K.; Hosoda, M.; Yamada, N.; Ishizuka, S.; Yoshino, A.; Yasuda, H.; Takahashi, H.; Nishimura, H. Erythromycin inhibits rhinovirus infection in cultured human tracheal epithelial cells. Am. J. Respir. Crit. Care Med. 2002, 165, 1113– 1118,  DOI: 10.1164/ajrccm.165.8.2103094
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    11
    Erythromycin inhibits rhinovirus infection in cultured human tracheal epithelial cells
    Suzuki Tomoko; Yamaya Mutsuo; Sekizawa Kiyohisa; Hosoda Masayoshi; Yamada Norihiro; Ishizuka Satoshi; Yoshino Akiko; Yasuda Hiroyasu; Takahashi Hidenori; Nishimura Hidekazu; Sasaki Hidetada
    American journal of respiratory and critical care medicine (2002), 165 (8), 1113-8 ISSN:1073-449X.
    To examine the effects of erythromycin on rhinovirus (RV) infection in airway epithelium, primary cultures of human tracheal epithelial cells were infected with the RV major subgroup, RV14, and the minor subgroup, RV2. Infection was confirmed by increases in viral RNA of the infected cells and viral titers of the supernatants. RV14 upregulated the expression of the mRNA and protein of intercellular adhesion molecule-1 (ICAM-1), the major RV receptor, and it increased the cytokine production. Erythromycin reduced the supernatant RV14 titers, RV14 RNA, the susceptibility to RV14 infection, and the production of ICAM-1 and cytokines. Erythromycin also reduced the supernatant RV2 titers, RV2 RNA, the susceptibility to RV2 infection, and cytokine production, although the inhibitory effects of erythromycin on the expression of the low-density lipoprotein receptor, the minor RV receptor, were small. Erythromycin reduced the nuclear factor-kappaB activation by RV14 and decreased the number of acidic endosomes in the epithelial cells. These results suggest that erythromycin inhibits infection by the major RV subgroup by reducing ICAM-1 and infection by both RV subgroups by blocking the RV RNA entry into the endosomes. Erythromycin may also modulate airway inflammation by reducing the production of proinflammatory cytokines and ICAM-1 induced by RV infection.
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  12. 12
    Jang, Y. J.; Kwon, H. J.; Lee, B. J. Effect of clarithromycin on rhinovirus-16 infection in A549 cells. Eur. Respir. J. 2006, 27, 12– 19,  DOI: 10.1183/09031936.06.00008005
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    12
    Effect of clarithromycin on rhinovirus-16 infection in A549 cells
    Jang, Y. J.; Kwon, H.-J.; Lee, B.-J.
    European Respiratory Journal (2006), 27 (1), 12-19CODEN: ERJOEI; ISSN:0903-1936. (European Respiratory Society)
    Clarithromycin (CM) has been found to inhibit the prodn. of the intercellular adhesion mol. (ICAM)-1 and the secretion of interleukin (IL)-6 and IL-8, which may have beneficial effects on the pathophysiol. changes related to rhinovirus (RV) infection. The effect of CM on RV infection in A549 cells was therefore investigated. Cells were pre-treated with 1, 10 or 100 μM CM, either starting 3 days before infection and continuing thereafter, or by addn. at the time of infection. RV titer, as measured by culture on Medical Research Council 5 cells, was reduced by CM, with the degree of redn. being greater when CM was added 3 days before infection than when it was added at the time of infection. CM treatment inhibited the RV-induced increase in ICAM-1 mRNA and protein, as well as the RV-induced secretion of IL-1β, IL-6, and IL-8. These effects were greater in cells treated with 10 μM than in those treated with 100 μM CM, and the max. effect was obsd. 3 days after viral infection. In contrast, secretion of IL-8 was not inhibited significantly when CM was added at the time of viral infection. The findings of this study suggest that, in A549 cells, clarithromycin inhibits the induction of intercellular adhesion mol.-1 expression, cytokine elaboration, and viral infection.
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  13. 13
    Yamaya, M.; Shinya, K.; Hatachi, Y.; Kubo, H.; Asada, M.; Yasuda, H.; Nishimura, H.; Nagatomi, R. Clarithromycin inhibits type a seasonal influenza virus infection in human airway epithelial cells. J. Pharmacol. Exp. Ther. 2010, 333, 81– 90,  DOI: 10.1124/jpet.109.162149
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    13
    Clarithromycin inhibits type A seasonal influenza virus infection in human airway epithelial cells
    Yamaya, Mutsuo; Shinya, Kyoko; Hatachi, Yukimasa; Kubo, Hiroshi; Asada, Masanori; Yasuda, Hiroyasu; Nishimura, Hidekazu; Nagatomi, Ryoichi
    Journal of Pharmacology and Experimental Therapeutics (2010), 333 (1), 81-90CODEN: JPETAB; ISSN:0022-3565. (American Society for Pharmacology and Experimental Therapeutics)
    Human influenza viruses attach to sialic acid with an α2,6 linkage (SAα2,6Gal) on the airway epithelial cells, and the entry of the viruses into the cells and uncoating of the viruses require low pH of endosomes. Bafilomycin A1, a macrolide antibiotic and a specific inhibitor of vacuolar H+-ATPase, inhibits growth of type A and type B human influenza viruses in Madin-Darby canine kidney cells. However, the inhibitory effects of clin. used macrolide antibiotics on influenza virus infection in human airways have not been studied. To examine the effects of clarithromycin on seasonal human influenza virus infection, cultured human tracheal epithelial cells were infected with type A influenza virus (H3N2). Influenza virus infection increased viral titers and the content of cytokines, including interleukin (IL)-1β and IL-6, in supernatant fluids, and viral RNA in the cells. Clarithromycin reduced viral titers and the content of cytokines in supernatant fluids, viral RNA in the cells, and the susceptibility to virus infection. Clarithromycin reduced the expression of SAα2,6Gal, a receptor for human influenza virus, on the mucosal surface of human tracheae, and the no. and fluorescence intensity of acidic endosomes in the cells from which viral ribonucleoproteins enter into the cytoplasm. Furthermore, clarithromycin reduced nuclear factor-κB (NF-κB) proteins, including p50 and p65, in the nuclear exts. These results suggest that clarithromycin may inhibit seasonal human influenza virus infection by reducing SAα2,6Gal partly through the inhibition of NF-κB, and increasing pH in endosomes in airway epithelial cells. Clarithromycin may modulate airway inflammation in influenza virus infection.
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  14. 14
    Lee, N.; Wong, C.; Chan, M. C.; Yeung, E. S.; Tam, W. W.; Tsang, O. T.; Choi, K.; Chan, P. K.; Kwok, A.; Lui, G. C. Anti-inflammatory effects of adjunctive macrolide treatment in adults hospitalized with influenza: a randomized controlled trial. Antiviral Res. 2017, 144, 48– 56,  DOI: 10.1016/j.antiviral.2017.05.008
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    14
    Anti-inflammatory effects of adjunctive macrolide treatment in adults hospitalized with influenza: A randomized controlled trial
    Lee, Nelson; Wong, Chun-Kwok; Chan, Martin C. W.; Yeung, Esther S. L.; Tam, Wilson W. S.; Tsang, Owen T. Y.; Choi, Kin-Wing; Chan, Paul K. S.; Kwok, Angela; Lui, Grace C. Y.; Leung, Wai-Shing; Yung, Irene M. H.; Wong, Rity Y. K.; Cheung, Catherine S. K.; Hui, David S. C.
    Antiviral Research (2017), 144 (), 48-56CODEN: ARSRDR; ISSN:0166-3542. (Elsevier B.V.)
    - Macrolides can ameliorate inflammation in respiratory diseases, providing clin. benefits. Data in influenza is lacking.- A randomized, open-label, multicenter trial among adults hospitalized for lab.-confirmed influenza was conducted. Study treatments of oseltamivir and azithromycin (500 mg/day), or oseltamivir alone, both for 5 days, were allocated at 1:1 ratio. The primary outcome was plasma cytokine/chemokine concn. change over time (Day 0-10); secondary outcomes were viral load and symptom score changes. Generalized Estg. Equation (GEE) models were used to analyze longitudinal data.- Fifty patients were randomized to the oseltamivir-azithromycin or oseltamivir groups, with comparable baseline characteristics (age, 57 ± 18 years; A/H3N2, 70%), complications (72%), and viral load. Pro-inflammatory cytokines IL-6 (GEE: β -0.037, 95%CI-0.067,-0.007, P = 0.016; redn. from baseline -83.4% vs -59.5%), CXCL8/IL-8 (β -0.018, 95%CI-0.037,0.000, P = 0.056; -80.5% vs -58.0%), IL-17 (β -0.064, 95%CI-0.117,-0.012, P = 0.015; -74.0% vs -34.3%), CXCL9/MIG (β -0.010, 95%CI-0.020,0.000, P = 0.043; -71.3% vs -56.0%), sTNFR-1, IL-18, and CRP declined faster in the oseltamivir-azithromycin group. There was a trend toward faster symptom resoln. (β -0.463, 95%CI-1.297,0.371). Viral RNA decline (P = 0.777) and culture-negativity rates were unaffected. Addnl. ex vivo studies confirmed reduced induction of IL-6 (P = 0.017) and CXCL8/IL-8 (P = 0.005) with azithromycin.- We found significant anti-inflammatory effects with adjunctive macrolide treatment in adults with severe influenza infections. Virus control was unimpaired. Clin. benefits of a macrolide-contg. regimen deserve further study.[ClinicalTrials.gov NCT01779570].
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    Bermejo-Martin, J. F.; Kelvin, D. J.; Eiros, J. M.; Castrodeza, J.; De Lejarazu, R. O. Macrolides for the treatment of severe respiratory illness caused by novel H1N1 swine influenza viral strains. J. Infect. Dev. Ctries. 2009, 3, 159– 161,  DOI: 10.3855/jidc.18
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    15
    Macrolides for the treatment of severe respiratory illness caused by novel H1N1 swine influenza viral strains
    Bermejo-Martin, Jesus F.; Kelvin, David J.; Eiros, Jose Maria; Castrodeza, Javier; de Lejarazu, Raul Ortiz
    Journal of Infection in Developing Countries (2009), 3 (3), 159-161CODEN: JIDCB9; ISSN:1972-2680. (OLoEP)
    A review. This paper presents the utilization of macrolides in the treatment of severe disease caused by the novel H1N1 swine flu reassortment influenza viruses. It has been proposed that macrolides be used in combination with antivirals, in order to diminish the systemic inflammatory response leading to pneumonia and fatal outcome. Macrolides are easy accessible: they are used in the hospitals of both developed and developing countries to treat bacterial infection; they are relatively cheap; and they show a good toxicity profile. Administration could be employed on the basis of a clin. score including high fever, chest X-ray images and O2 satn. as predictors for disease outcome.
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  16. 16
    Lendermon, E. A.; Coon, T. A.; Bednash, J. S.; Weathington, N. M.; McDyer, J. F.; Mallampalli, R. K. Azithromycin decreases NALP3 mRNA stability in monocytes to limit inflammasome-dependent inflammation. Respir. Res. 2017, 18, 1– 8,  DOI: 10.1186/s12931-017-0608-8
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    Gautret, P.; Lagier, J.; Parola, P.; Meddeb, L.; Mailhe, M.; Doudier, B.; Courjon, J.; Giordanengo, V.; Vieira, V. E.; Dupont, H. T. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Int. J. Antimicrob. Agents 2020, 56, 105949  DOI: 10.1016/j.ijantimicag.2020.105949
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    17
    Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial
    Gautret, Philippe; Lagier, Jean-Christophe; Parola, Philippe; Hoang, Van Thuan; Meddeb, Line; Mailhe, Morgane; Doudier, Barbara; Courjon, Johan; Giordanengo, Valerie; Vieira, Vera Esteves; Tissot Dupont, Herve; Honore, Stephane; Colson, Philippe; Chabriere, Eric; La Scola, Bernard; Rolain, Jean-Marc; Brouqui, Philippe; Raoult, Didier
    International Journal of Antimicrobial Agents (2020), 56 (1), 105949CODEN: IAAGEA; ISSN:0924-8579. (Elsevier B.V.)
    Background: Chloroquine and hydroxychloroquine have been found to be efficient on SARS-CoV-2, and reported to be efficient in Chinese COV-19 patients. We evaluate the effect of hydroxychloroquine on respiratory viral loads. Patients and Methods: French Confirmed COVID-19 patients were included in a single arm protocol from early March to March 16th, to receive 600mg of hydroxychloroquine daily and their viral load in nasopharyngeal swabs was tested daily in a hospital setting. Depending on their clin. presentation, azithromycin was added to the treatment. Untreated patients from another center and cases refusing the protocol were included as neg. controls. Presence and absence of virus at Day6-post inclusion was considered the end point. Results: Six patients were asymptomatic, 22 had upper respiratory tract infection symptoms and eight had lower respiratory tract infection symptoms. Twenty cases were treated in this study and showed a significant redn. of the viral carriage at D6-post inclusion compared to controls, and much lower av. carrying duration than reported in the literature for untreated patients. Azithromycin added to hydroxychloroquine was significantly more efficient for virus elimination. Conclusions: Despite its small sample size, our survey shows that hydroxychloroquine treatment is significantly assocd. with viral load redn./disappearance in COVID-19 patients and its effect is reinforced by azithromycin.
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  18. 18
    Gautret, P.; Lagier, J.; Parola, P.; Meddeb, L.; Sevestre, J.; Mailhe, M.; Doudier, B.; Aubry, C.; Amrane, S.; Seng, P. Clinical and microbiological effect of a combination of hydroxychloroquine and azithromycin in 80 COVID-19 patients with at least a six-day follow up: a pilot observational study. Travel Med.Infect. Dis. 2020, 34, 101663  DOI: 10.1016/j.tmaid.2020.101663
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    18
    Clinical and microbiological effect of a combination of hydroxychloroquine and azithromycin in 80 COVID-19 patients with at least a six-day follow up: A pilot observational study
    Gautret Philippe; Parola Philippe; Eldin Carole; Fournier Pierre Edouard; Lagier Jean-Christophe; Tissot-Dupont Herve Tissot; Stein Andreas; Million Matthieu; Colson Philippe; La Scola Bernard; Drancourt Michel; Rolain Jean-Marc; Brouqui Philippe; Hoang Van Thuan; Meddeb Line; Sevestre Jacques; Mailhe Morgane; Doudier Barbara; Aubry Camille; Amrane Sophie; Seng Piseth; Hocquart Marie; Vieira Vera Esteves; Finance Julie; Honore Stephane; Veit Veronique; Jacquier Alexis; Deharo Jean-Claude; Raoult Didier
    Travel medicine and infectious disease (2020), 34 (), 101663 ISSN:.
    BACKGROUND: We need an effective treatment to cure COVID-19 patients and to decrease virus carriage duration. METHODS: We conducted an uncontrolled, non-comparative, observational study in a cohort of 80 relatively mildly infected inpatients treated with a combination of hydroxychloroquine and azithromycin over a period of at least three days, with three main measurements: clinical outcome, contagiousness as assessed by PCR and culture, and length of stay in infectious disease unit (IDU). RESULTS: All patients improved clinically except one 86 year-old patient who died, and one 74 year-old patient still in intensive care. A rapid fall of nasopharyngeal viral load was noted, with 83% negative at Day7, and 93% at Day8. Virus cultures from patient respiratory samples were negative in 97.5% of patients at Day5. Consequently patients were able to be rapidly discharged from IDU with a mean length of stay of five days. CONCLUSION: We believe there is urgency to evaluate the effectiveness of this potentially-life saving therapeutic strategy at a larger scale, both to treat and cure patients at an early stage before irreversible severe respiratory complications take hold and to decrease duration of carriage and avoid the spread of the disease. Furthermore, the cost of treatment is negligible.
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  19. 19
    Cavalcanti, A. B.; Zampieri, F. G.; Rosa, R. G.; Azevedo, L. C.; Veiga, V. C.; Avezum, A.; Damiani, L. P.; Marcadenti, A.; Kawano-Dourado, L.; Lisboa, T. Hydroxychloroquine with or without Azithromycin in Mild-to-Moderate Covid-19. N. Engl. J. Med. 2020, 383, 2041– 2052,  DOI: 10.1056/NEJMoa2019014
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    19
    Hydroxychloroquine with or without azithromycin in mild-to-moderate Covid-19
    Cavalcanti, A. B.; Zampieri, F. G.; Rosa, R. G.; Azevedo, L. C. P.; Veiga, V. C.; Avezum, A.; Damiani, L. P.; Marcadenti, A.; Kawano-Dourado, L.; Lisboa, T.; Junqueira, D. L. M.; de Barros e Silva, P. G. M.; Tramujas, L.; Abreu-Silva, E. O.; Laranjeira, L. N.; Soares, A. T.; Echenique, L. S.; Pereira, A. J.; Freitas, F. G. R.; Gebara, O. C. E.; Dantas, V. C. S.; Furtado, R. H. M.; Milan, E. P.; Golin, N. A.; Cardoso, F. F.; Maia, I. S.; Filho, C. R. Hoffmann; Kormann, A. P. M.; Amazonas, R. B.; Bocchi de Oliveira, M. F.; Serpa-Neto, A.; Falavigna, M.; Lopes, R. D.; Machado, F. R.; Berwanger, O.
    New England Journal of Medicine (2020), 383 (21), 2041-2052CODEN: NEJMAG; ISSN:1533-4406. (Massachusetts Medical Society)
    Hydroxychloroquine and azithromycin have been used to treat patients with coronavirus disease 2019 (Covid-19). However, evidence on the safety and efficacy of these therapies is limited. We conducted a multicenter, randomized, open-label, three-group, controlled trial involving hospitalized patients with suspected or confirmed Covid-19 who were receiving either no supplemental oxygen or a max. of 4 L per min of supplemental oxygen. Patients were randomly assigned in a 1:1:1 ratio to receive std. care, std. care plus hydroxychloroquine at a dose of 400 mg twice daily, or std. care plus hydroxychloroquine at a dose of 400 mg twice daily plus azithromycin at a dose of 500 mg once daily for 7 days. The primary outcome was clin. status at 15 days as assessed with the use of a seven-level ordinal scale (with levels ranging from one to seven and higher scores indicating a worse condition) in the modified intention-to-treat population (patients with a confirmed diagnosis of Covid-19). Safety was also assessed. A total of 667 patients underwent randomization; 504 patients had confirmed Covid-19 and were included in the modified intention-to-treat anal. As compared with std. care, the proportional odds of having a higher score on the seven-point ordinal scale at 15 days was not affected by either hydroxychloroquine alone (odds ratio, 1.21; 95% confidence interval [CI], 0.69 to 2.11; P = 1.00) or hydroxychloroquine plus azithromycin (odds ratio, 0.99; 95% CI, 0.57 to 1.73; P = 1.00). Prolongation of the cor. QT interval and elevation of liver-enzyme levels were more frequent in patients receiving hydroxychloroquine, alone or with azithromycin, than in those who were not receiving either agent. Among patients hospitalized with mild-to-moderate Covid-19, the use of hydroxychloroquine, alone or with azithromycin, did not improve clin. status at 15 days as compared with std. care.
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  20. 20
    Rosenberg, E. S.; Dufort, E. M.; Udo, T.; Wilberschied, L. A.; Kumar, J.; Tesoriero, J.; Weinberg, P.; Kirkwood, J.; Muse, A.; DeHovitz, J. Association of treatment with hydroxychloroquine or azithromycin with in-hospital mortality in patients with COVID-19 in New York State. JAMA 2020, 323, 2493– 2502,  DOI: 10.1001/jama.2020.8630
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    20
    Association of treatment with hydroxychloroquine or azithromycin with in-hospital mortality in patients with COVID-19 in New York State
    Rosenberg, Eli S.; Dufort, Elizabeth M.; Udo, Tomoko; Wilberschied, Larissa A.; Kumar, Jessica; Tesoriero, James; Weinberg, Patti; Kirkwood, James; Muse, Alison; DeHovitz, Jack; Blog, Debra S.; Hutton, Brad; Holtgrave, David R.; Zucker, Howard A.
    JAMA, the Journal of the American Medical Association (2020), 323 (24), 2493-2502CODEN: JAMAAP; ISSN:1538-3598. (American Medical Association)
    Hydroxychloroquine, with or without azithromycin, has been considered as a possible therapeutic agent for patients with coronavirus disease 2019 (COVID-19). However, there are limited data on efficacy and assocd. adverse events. To describe the assocn. between use of hydroxychloroquine, with or without azithromycin, and clin. outcomes among hospital inpatients diagnosed with COVID-19. Retrospective multicenter cohort study of patients from a random sample of all admitted patients with lab.-confirmed COVID-19 in 25 hospitals, representing 88.2% of patients with COVID-19 in the New York metropolitan region. Eligible patients were admitted for at least 24 h between March 15 and 28, 2020. Medications, preexisting conditions, clin. measures on admission, outcomes, and adverse events were abstracted from medical records. The date of final follow-up was Apr. 24, 2020. exposures Receipt of both hydroxychloroquine and azithromycin, hydroxychloroquine alone, azithromycin alone, or neither. main outcomes and measures Primary outcome was in-hospital mortality. Secondary outcomes were cardiac arrest and abnormal ECG findings (arrhythmia or QT prolongation). Among 1438 hospitalized patients with a diagnosis of COVID-19 (858 [59.7%] male, median age, 63 years), those receiving hydroxychloroquine, azithromycin, or both were more likely than those not receiving either drug to have diabetes, respiratory rate >22/min, abnormal chest imaging findings, O2 satn. lower than 90%, and aspartate aminotransferase greater than 40 U/L. Overall in-hospital mortality was 20.3% (95% CI, 18.2%-22.4%). The probability of death for patients receiving hydroxychloroquine + azithromycin was 189/735 (25.7% [95% CI, 22.3%-28.9%]), hydroxychloroquine alone, 54/271 (19.9% [95% CI, 15.2%-24.7%]), azithromycin alone, 21/211 (10.0% [95% CI, 5.9%-14.0%]), and neither drug, 28/221 (12.7% [95% CI, 8.3%-17.1%]). In adjusted Cox proportional hazards models, compared with patients receiving neither drug, there were no significant differences in mortality for patients receiving hydroxychloroquine + azithromycin (HR, 1.35 [95% CI, 0.76-2.40]), hydroxychloroquine alone (HR, 1.08 [95% CI, 0.63-1.85]), or azithromycin alone (HR, 0.56 [95% CI, 0.26-1.21]). In logistic models, compared with patients receiving neither drug cardiac arrest was significantly more likely in patients receiving hydroxychloroquine + azithromycin (adjusted OR, 2.13 [95% CI, 1.12-4.05]), but not hydroxychloroquine alone (adjusted OR, 1.91 [95% CI, 0.96-3.81]) or azithromycin alone (adjusted OR, 0.64 [95% CI, 0.27-1.56]),. In adjusted logistic regression models, there were no significant differences in the relative likelihood of abnormal ECG findings. conclusions and relevance Among patients hospitalized in metropolitan New York with COVID-19, treatment with hydroxychloroquine, azithromycin, or both, compared with neither treatment, was not significantly assocd. with differences in in-hospital mortality. However, the interpretation of these findings may be limited by the observational design.
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  21. 21
    Furtado, R. H. M.; Berwanger, O.; Fonseca, H. A.; Corrêa, T. D.; Ferraz, L. R.; Lapa, M. G.; Zampieri, F. G.; Veiga, V. C.; Azevedo, L. C.; Rosa, R. G. Azithromycin in addition to standard of care versus standard of care alone in the treatment of patients admitted to the hospital with severe COVID-19 in Brazil (COALITION II): a randomised clinical trial. Lancet 2020, 396, 959– 967,  DOI: 10.1016/S0140-6736(20)31862-6
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    21
    Azithromycin in addition to standard of care versus standard of care alone in the treatment of patients admitted to the hospital with severe COVID-19 in Brazil (COALITION II): a randomised clinical trial
    Furtado, Remo H. M.; Berwanger, Otavio; Fonseca, Henrique A.; Correa, Thiago D.; Ferraz, Leonardo R.; Lapa, Maura G.; Zampieri, Fernando G.; Veiga, Viviane C.; Azevedo, Luciano C. P.; Rosa, Regis G.; Lopes, Renato D.; Avezum, Alvaro; Manoel, Airton L. O.; Piza, Felipe M. T.; Martins, Priscilla A.; Lisboa, Thiago C.; Pereira, Adriano J.; Olivato, Guilherme B.; Dantas, Vicente C. S.; Milan, Eveline P.; Gebara, Otavio C. E.; Amazonas, Roberto B.; Oliveira, Monalisa B.; Soares, Ronaldo V. P.; Moia, Diogo D. F.; Piano, Luciana P. A.; Castilho, Kleber; Momesso, Roberta G. R. A. P.; Schettino, Guilherme P. P.; Rizzo, Luiz Vicente; Neto, Ary Serpa; Machado, Flavia R.; Cavalcanti, Alexandre B.
    Lancet (2020), 396 (10256), 959-967CODEN: LANCAO; ISSN:0140-6736. (Elsevier Ltd.)
    The efficacy and safety of azithromycin in the treatment of COVID-19 remain uncertain. We assessed whether adding azithromycin to std. of care, which included hydroxychloroquine, would improve clin. outcomes of patients admitted to the hospital with severe COVID-19. We did an open-label, randomised clin. trial at 57 centers in Brazil. We enrolled patients admitted to hospital with suspected or confirmed COVID-19 and at least one addnl. severity criteria as follows: use of oxygen supplementation of more than 4 L/min flow; use of high-flow nasal cannula; use of non-invasive mech. ventilation; or use of invasive mech. ventilation. Patients were randomly assigned (1:1) to azithromycin (500 mg via oral, nasogastric, or i.v. administration once daily for 10 days) plus std. of care or to std. of care without macrolides. All patients received hydroxychloroquine (400 mg twice daily for 10 days) because that was part of std. of care treatment in Brazil for patients with severe COVID-19. The primary outcome, assessed by an independent adjudication committee masked to treatment allocation, was clin. status at day 15 after randomisation, assessed by a six-point ordinal scale, with levels ranging from 1 to 6 and higher scores indicating a worse condition (with odds ratio [OR] greater than 1·00 favoring the control group). The primary outcome was assessed in all patients in the intention-to-treat (ITT) population who had severe acute respiratory syndrome coronavirus 2 infection confirmed by mol. or serol. testing before randomisation (ie, modified ITT [mITT] population). Safety was assessed in all patients according to which treatment they received, regardless of original group assignment. This trial was registered at ClinicalTrials.gov, NCT04321278.447 patients were enrolled from March 28 to May 19, 2020. COVID-19 was confirmed in 397 patients who constituted the mITT population, of whom 214 were assigned to the azithromycin group and 183 to the control group. In the mITT population, the primary endpoint was not significantly different between the azithromycin and control groups (OR 1·36 [95% CI 0·94-1·97], p=0·11). Rates of adverse events, including clin. relevant ventricular arrhythmias, resuscitated cardiac arrest, acute kidney failure, and cor. QT interval prolongation, were not significantly different between groups. In patients with severe COVID-19, adding azithromycin to std. of care treatment (which included hydroxychloroquine) did not improve clin. outcomes. Our findings do not support the routine use of azithromycin in combination with hydroxychloroquine in patients with severe COVID-19. COALITION COVID-19 Brazil and EMS.
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    Zanni, R.; Galvez-Llompart, M.; Garcia-Domenech, R.; Galvez, J. Latest advances in molecular topology applications for drug discovery. Expert Opin. Drug Discov. 2015, 10, 945– 957,  DOI: 10.1517/17460441.2015.1062751
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    Latest advances in molecular topology applications for drug discovery
    Zanni, Riccardo; Galvez-Llompart, Maria; Garcia-Domenech, Ramon; Galvez, Jorge
    Expert Opinion on Drug Discovery (2015), 10 (9), 945-957CODEN: EODDBX; ISSN:1746-0441. (Taylor & Francis Ltd.)
    Mol. topol. (MT) has emerged in recent years as a powerful approach for the in silico generation of new drugs. In the last decade, its application has become more and more popular among the leading research groups in the field of quant. structure-activity relationships (QSAR) and drug design. This has, in turn, contributed to the rapid development of new techniques and applications of MT in QSAR studies, as well as the introduction of new topol. indexes. This review collates the main innovative techniques in the field of MT and provides a description of the novel topol. indexes recently introduced, through an exhaustive recompilation of the most significant works carried out by the leading research groups in the field of drug design and discovery. The objective is to show the importance of MT methods combined with the effectiveness of the descriptors. Recent years have witnessed a remarkable rise in QSAR methods based on MT and its application to drug design. New methodologies have been introduced in the area such as QSAR multi-target, Markov networks or perturbation methods. Moreover, novel topol. indexes, such as Bourgas' descriptors and other new concepts as the deriv. of a graph or cliques capable to distinguish between conformers, have also been introduced. New drugs have also been discovered, including anticonvulsants, anineoplastics, antimalarials or antiallergics, just to name a few. In the authors' opinion, MT and QSAR have moved from an attractive possibility to representing a foundation stone in the process of drug discovery.
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    Sajib, A. Repurposing of Approved Drugs with Potential to Block SARS-CoV-2 Surface Glycoprotein Interaction with Host Receptor. Preprints 2020, 2020040369,  DOI: 10.20944/preprints202004.0369.v1
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    Garle, M. J.; Fentem, J. H.; Fry, J. R.
    Toxicology in Vitro (1994), 8 (6), 1303-12CODEN: TIVIEQ; ISSN:0887-2333. (Elsevier)
    A review with many refs. The use of in vitro cytotoxicity tests for the prediction of acute toxicity in vivo was reviewed.
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    Tyteca, D.; Van Der Smissen, P.; Van Bambeke, F.; Leys, K.; Tulkens, P. M.; Courtoy, P. J.; Mingeot-Leclercq, M. Azithromycin, a lysosomotropic antibiotic, impairs fluid-phase pinocytosis in cultured fibroblasts. Eur. J. Cell Biol. 2001, 80, 466– 478,  DOI: 10.1078/0171-9335-00180
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    Azithromycin, a lysosomotropic antibiotic, impairs fluid-phase pinocytosis in cultured fibroblasts
    Tyteca, Donatienne; Van Der Smissen, Patrick; Van Bambeke, Francoise; Leys, Karin; Tulkens, Paul M.; Courtoy, Pierre J.; Mingeot-Leclercq, Marie-Paule
    European Journal of Cell Biology (2001), 80 (7), 466-478CODEN: EJCBDN; ISSN:0171-9335. (Urban & Fischer Verlag)
    The dicationic macrolide antibiotic azithromycin inhibited the uptake of horseradish peroxidase (HRP) by fluid-phase pinocytosis into fetal rat fibroblasts in a time- and concn.-dependent fashion without affecting its decay (regurgitation and/or degrdn.). The azithromycin effect was additive to that of nocodazole, known to impair endocytic uptake and transport of solutes along the endocytic pathway. Cytochem. (light and electron microscopy) showed a major redn. by azithromycin of the no. of HRP-labeled endocytic vesicles after 5 min (endosomes) and 2 h (lysosomes). Within 3 h of exposure, azithromycin also caused the appearance of large and light-lucent/electron-lucent vacuoles, most of which could be labeled by lucifer yellow when this tracer was added to culture prior to azithromycin exposure. Three days of treatment with azithromycin resulted in the accumulation of very large vesicles filled with pleiomorphic content, consistent with phospholipidosis. These vesicles were accessible to fluorescein-labeled bovine serum albumin and were intensively stained with filipin, indicating a mixed storage with cholesterol. The impairment of HRP pinocytosis directly correlated with the amt. of azithromycin accumulated by the cells, but not with the phospholipidosis induced by the drug. The proton ionophore monensin, which completely suppressed azithromycin accumulation, also prevented the inhibition of HRP uptake. Erythromycylamine, another dicationic macrolide, also inhibited HRP pinocytosis in direct correlation with its cellular accumulation and was as potent as azithromycin at equimolar cellular concns. It is suggested that dicationic macrolides inhibit fluid-phase pinocytosis by impairing the formation of pinocytotic vacuoles and endosomes.
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    Tyteca, D.; Van Der Smissen, P.; Mettlen, M.; Van Bambeke, F.; Tulkens, P. M.; Mingeot-Leclercq, M.; Courtoy, P. J. Azithromycin, a lysosomotropic antibiotic, has distinct effects on fluid-phase and receptor-mediated endocytosis, but does not impair phagocytosis in J774 macrophages. Exp. Cell Res. 2002, 281, 86– 100,  DOI: 10.1006/excr.2002.5613
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    Azithromycin, a Lysosomotropic Antibiotic, Has Distinct Effects on Fluid-Phase and Receptor-Mediated Endocytosis, but Does Not Impair Phagocytosis in J774 Macrophages
    Tyteca, Donatienne; Van Der Smissen, Patrick; Mettlen, Marcel; Van Bambeke, Francoise; Tulkens, Paul M.; Mingeot-Leclercq, Marie-Paule; Courtoy, Pierre J.
    Experimental Cell Research (2002), 281 (1), 86-100CODEN: ECREAL; ISSN:0014-4827. (Elsevier Science)
    Pretreatment of J774 mouse macrophages by the dicationic macrolide antibiotic, azithromycin (AZ), selectively inhibited fluid-phase endocytosis of horseradish peroxidase and lucifer yellow, but not phagocytosis of latex beads. AZ delayed sequestration of receptor-bound transferrin and peroxidase-anti-peroxidase immune complexes into cell-surface endocytic pits and vesicles, but did not slow down the subsequent rate of receptor-mediated endocytosis. AZ down-regulated cell surface transferrin receptors, but not Fcγ receptors, by causing a major delay in the accessibility of internalized transferrin receptors to the recycling route, without slowing down subsequent efflux, resulting in redistribution of the surface pool to an intracellular pool. Acidotropic accumulation of AZ was assocd. with an extensive vacuolation of late endosomes/lysosomes, and these compartments became unaccessible to horseradish peroxidase and immune complexes, but not to latex beads. The inhibitory profile of AZ cannot be solely accounted for by vacuolation and interference with acidification. AZ may help in dissecting various steps of the endocytic app. such as lateral mobility of receptors at the plasma membrane, formation of clathrin-independent endocytic vesicles, orientation of transferrin receptors into the recycling route, and fusogenicity with lysosomes.
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    Gastaminza, P.; Whitten-Bauer, C.; Chisari, F. V. Unbiased probing of the entire hepatitis C virus life cycle identifies clinical compounds that target multiple aspects of the infection. Proc. Natl. Acad. Sci. 2010, 107, 291– 296,  DOI: 10.1073/pnas.0912966107
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    28
    Unbiased probing of the entire hepatitis C virus life cycle identifies clinical compounds that target multiple aspects of the infection
    Gastaminza, Pablo; Whitten-Bauer, Christina; Chisari, Francis V.
    Proceedings of the National Academy of Sciences of the United States of America (2010), 107 (1), 291-296, S291/1-S291/32CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
    Over 170 million people are chronically infected by the hepatitis C virus (HCV) and at risk for dying from liver cirrhosis and hepatocellular carcinoma. Current therapy is expensive, assocd. with significant side effects, and often ineffective. Discovery of antiviral compds. against HCV traditionally involves a priori target identification followed by biochem. screening and confirmation in cell-based replicon assays. Typically, this results in the discovery of compds. that address a few predetd. targets and are prone to select for escape variants. To attempt to identify antiviral compds. with broad target specificity, we developed an unbiased cell-based screening system involving multiple rounds of infection in a 96-well fonnat. Anal. of a publicly available library of 446 clin. approved drugs identified 33 compds. that targeted both known and previously unexplored aspects of HCV infection, including entry, replication, and assembly. Discovery of novel viral and cellular targets in this manner will broaden the therapeutic armamentarium against this virus, allowing for the development of drug mixts. that should reduce the likelihood of mutational escape.
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  29. 29
    Mingorance, L.; Friesland, M.; Coto-Llerena, M.; Pérez-del-Pulgar, S.; Boix, L.; López-Oliva, J. M.; Bruix, J.; Forns, X.; Gastaminza, P. Selective inhibition of hepatitis C virus infection by hydroxyzine and benztropine. Antimicrob. Agents Chemother. 2014, 58, 3451– 3460,  DOI: 10.1128/AAC.02619-14
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    Selective inhibition of hepatitis C virus infection by hydroxyzine and benztropine
    Mingorance, Lidia; Friesland, Martina; Coto-Llerena, Mairene; Perez-del-Pulgar, Sofia; Boix, Loreto; Lopez-Oliva, Juan Manuel; Bruix, Jordi; Forns, Xavier; Gastaminza, Pablo
    Antimicrobial Agents and Chemotherapy (2014), 58 (6), 3451-3460, 11 pp.CODEN: AMACCQ; ISSN:1098-6596. (American Society for Microbiology)
    Hepatitis C virus (HCV) infection is a major biomedical problem worldwide as it causes severe liver disease in millions of humans around the world. Despite the recent approval of specific drugs targeting HCV replication to be used in combination with alpha interferon (IFN-α) and ribavirin, there is still an urgent need for pangenotypic, interferon-free therapies to fight this genetically diverse group of viruses. In this study, we used an unbiased screening cell culture assay to interrogate a chem. library of compds. approved for clin. use in humans. This system enables identifying nontoxic antiviral compds. targeting every aspect of the viral life cycle, be the target viral or cellular. The aim of this study was to identify drugs approved for other therapeutic applications in humans that could be effective components of combination therapies against HCV. As a result of this anal., we identified 12 compds. with antiviral activity in cell culture, some of which had previously been identified as HCV inhibitors with antiviral activity in cell culture and had been shown to be effective in patients. We selected two novel HCV antivirals, hydroxyzine and benztropine, to characterize them by detg. their specificity and genotype spectrum as well as by defining the step of the replication cycle targeted by these compds. We found that both compds. effectively inhibited viral entry at a postbinding step of genotypes 1, 2, 3, and 4 without affecting entry of other viruses.
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  30. 30
    Arikata, M.; Itoh, Y.; Shichinohe, S.; Nakayama, M.; Ishigaki, H.; Kinoshita, T.; Le, M. Q.; Kawaoka, Y.; Ogasawara, K.; Shimizu, T. Efficacy of clarithromycin against H5N1 and H7N9 avian influenza a virus infection in cynomolgus monkeys. Antiviral Res. 2019, 171, 104591  DOI: 10.1016/j.antiviral.2019.104591
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    Efficacy of clarithromycin against H5N1 and H7N9 avian influenza a virus infection in cynomolgus monkeys
    Arikata, Masahiko; Itoh, Yasushi; Shichinohe, Shintaro; Nakayama, Misako; Ishigaki, Hirohito; Kinoshita, Takaaki; Le, Mai Quynh; Kawaoka, Yoshihiro; Ogasawara, Kazumasa; Shimizu, Takeshi
    Antiviral Research (2019), 171 (), 104591CODEN: ARSRDR; ISSN:0166-3542. (Elsevier B.V.)
    Clarithromycin (CAM), a 14-membered ring macrolide, has anti-inflammatory and immunomodulatory actions and antiviral effects in seasonal influenza virus infection. We examd. the prophylactic and therapeutic efficacy of CAM against H5N1 highly pathogenic and H7N9 low pathogenic avian influenza virus infections in cynomolgus monkeys. CAM suppressed H5N1 virus-induced severe signs of disease in the treated monkeys and inhibited virus propagation in tracheal samples and the prodn. of inflammatory cytokines in the lungs of monkeys infected with H5N1 and H7N9 viruses. The prophylactic administration of CAM showed more suppressive effects on clin. signs of disease and viral titers than did therapeutic administration. Thus, since administration of CAM alone showed a tendency to ameliorate clin. sings and to reduce levels of inflammatory cytokines, the macrolides are expected to have effects in combination with the other antiviral drugs on the prophylactic and treatment of patients with severe avian influenza virus infection, which should be further investigated.
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    Kanatani, M. S.; Guglielmo, B. J. The new macrolides. Azithromycin and clarithromycin. West. J. Med. 1994, 92, 31– 282,  DOI: 10.1080/00325481.1992.11701404
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    Tiwari, V.; Beer, J. C.; Sankaranarayanan, N. V.; Swanson-Mungerson, M.; Desai, U. R. Discovering small-molecule therapeutics against SARS-CoV-2. Drug Discovery Today 2020, 1535,  DOI: 10.1016/j.drudis.2020.06.017
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    Discovering small-molecule therapeutics against SARS-CoV-2
    Tiwari, Vaibhav; Beer, Jacob C.; Sankaranarayanan, Nehru Viji; Swanson-Mungerson, Michelle; Desai, Umesh R.
    Drug Discovery Today (2020), 25 (8), 1535-1544CODEN: DDTOFS; ISSN:1359-6446. (Elsevier Ltd.)
    A review. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly become a global health pandemic. The lack of effective treatments, coupled with its etiol., has resulted in more than 400,000 deaths at the time of writing. The SARS-CoV-2 genome is highly homologous to that of SARS-CoV, the causative agent behind the 2003 SARS outbreak. Based on prior reports, clinicians have pursued the off-label use of several antiviral drugs, while the scientific community has responded by seeking agents against traditional targets, esp. viral proteases. However, several avenues remain unexplored, including disrupting E and M protein oligomerization, outcompeting host glycan-virus interactions, interfering with the heparan sulfate proteoglycans-virus interaction, and others. In this review, the authors highlight some of these opportunities while summarizing the drugs currently in use against coronavirus 2019 (COVID-19).
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    Huang, F.; Li, Y.; Leung, E. L.; Liu, X.; Liu, K.; Wang, Q.; Lan, Y.; Li, X.; Yu, H.; Cu, L. A review of therapeutic agents and Chinese herbal medicines against SARS-COV-2 (COVID-19). Pharmacol. Res. 2020, 158, 104929  DOI: 10.1016/j.phrs.2020.104929
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    A review of therapeutic agents and Chinese herbal medicines against SARS-COV-2 (COVID-19)
    Huang, Fangfang; Li, Ying; Leung, Elaine Lai-Han; Liu, Xiaohua; Liu, Kaifeng; Wang, Qu; Lan, Yongqi; Li, Xiaoling; Yu, Haibing; Cui, Liao; Luo, Hui; Luo, Lianxiang
    Pharmacological Research (2020), 158 (), 104929CODEN: PHMREP; ISSN:1043-6618. (Elsevier Ltd.)
    A review. The epidemic of pneumonia (COVID-19) caused by novel coronavirus (SARS-CoV-2) infection has been listed as a public health emergency of international concern by the World Health Organization (WHO), and its harm degree is defined as a global "pandemic". At present, the efforts of various countries focus on the rapid diagnosis and isolation of patients, as well as to find a treatment that can combat the most serious impact of the disease. The no. of reported COVID-19 virus infections is still increasing. Unfortunately, no drugs or vaccines have been approved for the treatment of human coronaviruses, but there is an urgent need for in-depth research on emerging human infectious coronaviruses. Clarification transmission routes and pathogenic mechanisms, and identification of potential drug treatment targets will promote the development of effective prevention and treatment measures. In the absence of confirmed effective treatments, due to public health emergencies, it is essential to study the possible effects of existing approved antivirals drugs or Chinese herbal medicines for SARS-CoV-2. This review summarizes the epidemiol. characteristics, pathogenesis, virus structure and targeting strategies of COVID-19. Meanwhile, this review also focus on the re-purposing of clin. approved drugs and Chinese herbal medicines that may be used to treat COVID-19 and provide new ideas for the discovery of small mol. compds. with potential therapeutic effects on novel COVID-19.
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    Jeong, G. U.; Song, H.; Yoon, G. Y.; Kim, D.; Kwon, Y.-C. Therapeutic strategies against COVID-19 and structural characterization of SARS-CoV-2: a review. Front. Microbiol. 2020, 11, 1723  DOI: 10.3389/fmicb.2020.01723
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    Therapeutic Strategies Against COVID-19 and Structural Characterization of SARS-CoV-2: A Review
    Jeong Gi Uk; Yoon Gun Young; Kwon Young-Chan; Song Hanra; Kim Doyoun
    Frontiers in microbiology (2020), 11 (), 1723 ISSN:1664-302X.
    The novel coronavirus, SARS-CoV-2, or 2019-nCoV, which originated in Wuhan, Hubei province, China in December 2019, is a grave threat to public health worldwide. A total of 3,672,238 confirmed cases of coronavirus disease 2019 (COVID-19) and 254,045 deaths were reported globally up to May 7, 2020. However, approved antiviral agents for the treatment of patients with COVID-19 remain unavailable. Drug repurposing of approved antivirals against other viruses such as HIV or Ebola virus is one of the most practical strategies to develop effective antiviral agents against SARS-CoV-2. A combination of repurposed drugs can improve the efficacy of treatment, and structure-based drug design can be employed to specifically target SARS-CoV-2. This review discusses therapeutic strategies using promising antiviral agents against SARS-CoV-2. In addition, structural characterization of potentially therapeutic viral or host cellular targets associated with COVID-19 have been discussed to refine structure-based drug design strategies.
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    Olah, M.; Oprea, T. I. Comprehensive Medicinal Chemistry II vol 3. Taylor, J. B.; Triggle, D. J. (eds). Bioactivity Databases. 2006.
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    Tandon, R.; Sharp, J. S.; Zhang, F.; Pomin, V. H.; Ashpole, N. M.; Mitra, D.; McCandless, M. G.; Jin, W.; Liu, H.; Sharma, P. Effective inhibition of SARS-CoV-2 entry by heparin and enoxaparin derivatives. J. Virol. 2021, 95, e01987– e01920,  DOI: 10.1128/JVI.01987-20
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    Effective inhibition of SARS-CoV-2 entry by heparin and enoxaparin derivatives
    Tandon, Ritesh; Sharp, Joshua S.; Zhang, Fuming; Pomin, Vitor H.; Ashpole, Nicole M.; Mitra, Dipanwita; McCandless, Martin G.; Jin, Weihua; Liu, Hao; Sharma, Poonam; Linhardt, Robert J.
    Journal of Virology (2021), 95 (3), e01987CODEN: JOVIAM; ISSN:1098-5514. (American Society for Microbiology)
    Severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) has caused a pandemic of historic proportions and continues to spread globally, with enormous consequences to human health. Currently there is no vaccine, effective therapeutic, or prophylactic. As with other betacoronaviruses, attachment and entry of SARS-CoV-2 are mediated by the spike glycoprotein (SGP). In addn. to its well-documented interaction with its receptor, human angiotensin-converting enzyme 2 (hACE2), SGP has been found to bind to glycosaminoglycans like heparan sulfate, which is found on the surface of virtually all mammalian cells. Here, we pseudotyped SARS-CoV-2 SGP on a third-generation lentiviral (pLV) vector and tested the impact of various sulfated polysaccharides on transduction efficiency in mammalian cells. The pLV vector pseudotyped SGP efficiently and produced high titers on HEK293T cells. Various sulfated polysaccharides potently neutralized pLV-S pseudotyped virus with clear structure-based differences in antiviral activity and affinity to SGP. Concn.-response curves showed that pLV-S particles were efficiently neutralized by a range of concns. of unfractionated heparin (UFH), enoxaparin, 6-O-desulfated UFH, and 6-O-desulfated enoxaparin with 50% inhibitory concns. (IC50s) of 5.99 μg/L, 1.08 mg/L, 1.77 μg/L, and 5.86 mg/L, resp. In summary, several sulfated polysaccharides show potent anti-SARS-CoV-2 activity and can be developed for prophylactic as well as therapeutic purposes.
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    Hoffmann, M.; Schroeder, S.; Kleine-Weber, H.; Müller, M. A.; Drosten, C.; Pöhlmann, S. Nafamostat mesylate blocks activation of SARS-CoV-2: new treatment option for COVID-19. Antimicrob. Agents Chemother. 2020, 64, e00754– e00720,  DOI: 10.1128/AAC.00754-20
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    Nafamostat mesylate blocks activation of SARS-CoV-2: new treatment option for COVID-19
    Hoffmann, Markus; Schroeder, Simon; Kleine-Weber, Hannah; Mueller, Marcel A.; Drosten, Christian; Poehlmanna, Stefan
    Antimicrobial Agents and Chemotherapy (2020), 64 (6), e00754/1-e00754/3CODEN: AMACCQ; ISSN:1098-6596. (American Society for Microbiology)
    The currently unfolding coronavirus pandemic threatens health systems and economies worldwide. The spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the assocd. disease coronavirus disease 2019 (COVID-19) has nitially been limited to China. However, the virus has now been detected in more than 100 countries outside China, and major outbreaks are ongoing in the United States, taly, and Spain. At present, our antiviral arsenal offers little protection against SARS CoV-2, although recent progress has been reported (1), and novel antivirals are urgently needed to mitigate the COVID-19 health crisis. The SARS-CoV-2 spike protein (S) is inserted into the viral envelope and mediates viral entry into cells. For this, the S protein depends on the cellular enzyme transmem brane protease serine 2 (TMPRSS2), which cleaves and thereby activates the S protein (2). SARS-CoV (3-5) and other coronaviruses (6, 7) also use TMPRSS2 for S protein activation, and the protease is expressed in SARS-CoV target cells throughout the human respiratory tract (8). Moreover, TMPRSS2 is required for spread of SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV) in rodent models (9, 10) but is dispensable for development and homeostasis in mice (11). Thus, TMPRSS2 consti tutes an attractive drug target. Recent work shows that camostat mesylate (NI-03), a serine protease inhibitor active against TMPRSS2 and employed for treatment of pancreatitis in Japan, inhibits SARS CoV-2 infection of human lung cells (2). The suitability of camostat mesylate for treatment of COVID-19 is currently being evaluated in a clin. trial (12), but it is unclear whether compd. concns. can be attained in the lung that are sufficient to suppress viral spread. In the absence of this information, testing of other serine protease inhibitors for blockade of SARS-CoV-2 entry is an important task. For this, we tested gabexate mesylate (FOY) and nafamostat mesylate (Futhan) (13) along with camostat mesylate for inhibition of SARS-CoV-2 infection of lung cells. All com pounds are approved for human use in Japan, and nafamostat mesylate inhibits TMPRSS2-dependent host cell entry of MERS-CoV (14). A comparison of the antiviral activities of the three compds. revealed that none interfered with cell viability or with host cell entry mediated by the glycoproteins of vesicular stomatitis virus or Machupo virus (Fig. 1A), which served as neg. controls. Gabexate mesylate slightly inhibited SARS-CoV-2 S-driven host cell entry while camostat mesylate robustly sup pressed entry (Fig. 1A). Notably, nafamostat mesylate, which is FDA approved for indications unrelated to coronavirus infection, inhibited SARS-CoV-2 S-mediated entry.
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    The rapid emergence of COVID-19 pandemics has posed humans particularly vulnerable to the novel SARS-CoV-2 virus. Since de novo drug discovery is both expensive and time-consuming, drug repurposing approaches are believed to be of particular help. The SARS-CoV-2 spike (S) protein is known to attach human angiotensin-converting enzyme-2 (hACE2) through its receptor-binding domain (RBD). We screened 1930 FDA-approved ligands for the selection of optimal ones blocking this interaction. Virtual screening predicted top 25 ligands docking to any of the reported binding sites. After exclusion of those ligands which were unsuitable for systemic use, the remaining 69 RBD-ligand complexes were screened based on the masking capacity of the amino acid residues engaged in RBD-hACE2 interaction, excluding 47 RBD-ligand complexes. A short molecular dynamics (MD) simulation analysis identified 11 globally stable complexes with the lowest RMSD (root-mean-square deviation). Next, a moderately long MD analysis revealed those six RBD-ligand complexes with the lowest RMSD variation, as a measure of global stability. Finally, a long MD analysis revealed two select candidate ligands, including ritonavir and naloxegol, highly stabilizing those key residues engaged in RBD-hACE2 interaction. A similar MD analysis of a few antiviral drugs which are under clinical trials or approved for COVID-19 treatment showed them inferior to both select ligands in terms of stabilizing the RBD globally and locally at binding sites. Because of the crucial role of the S protein in virus virulence, our results highly propose ritonavir and naloxegol as the potentially helpful therapeutics against COVID-19, mandating appropriate clinical trials. Communicated by Ramaswamy H. Sarma.
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    COVID-19, which has emerged recently as a pandemic viral infection caused by SARS-coronavirus 2 has spread rapidly around the world, creating a public health emergency. The current situation demands an effective therapeutic strategy to control the disease using drugs that are approved, or by inventing new ones. The present study examines the possible repurposing of existing anti-viral protease inhibitor drugs. For this, the structural features of the viral spike protein, the substrate for host cell protease and main protease of the available SARS CoV-2 isolates were established by comparing with related viruses for which antiviral drugs are effective. The results showed 97% sequence similarity among SARS and SARS-CoV-2 main protease and has same cleavage site positions and ACE2 receptor binding region as in the SARS-CoV spike protein. Though both are N-glycosylated, unlike SARS-CoV, human SARS-CoV-2 S-protein was O-glycosylated as well. Molecular docking studies were done to explore the role of FDA approved protease inhibitors to control SARS-CoV-2 replication. The results indicated that, Ritonavir has the highest potency to block SARS-CoV-2 main protease and human TMPRSS2, a host cell factor that aids viral infection. Other drugs such as Indinavir and Atazanavir also showed favourable binding with Cathepsin B/L that helped viral fusion with the host cell membrane. Further molecular dynamics simulation and MM-PBSA binding free energy calculations confirmed the stability of protein-drug complexes. These results suggest that protease inhibitors particularly Ritonavir, either alone or in combination with other drugs such as Atazanavir, have the potential to treat COVID 19. Communicated by Ramaswamy H. Sarma.
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  2. Riccardo Zanni, Maria Galvez-Llompart, Jorge Galvez. Computational analysis of macrolides as SARS-CoV-2 main protease inhibitors: a pattern recognition study based on molecular topology and validated by molecular docking. New Journal of Chemistry 2021, 45 (19) , 8654-8675. https://doi.org/10.1039/D0NJ05983H
  3. Belén Carro. SARS-CoV-2 mechanisms of action and impact on human organism, risk factors and potential treatments. An exhaustive survey. All Life 2021, 14 (1) , 894-947. https://doi.org/10.1080/26895293.2021.1977186

  • Abstract

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    Figure 1

    Figure 1. Example of SPI values for active and inactive molecules in the DF1 training set.

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    Figure 2

    Figure 2. PDD for DF1. Filled bars for the active and empty bars for the inactive.

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    Figure 3

    Figure 3. Example of GATS3i values for active and inactive molecules of the DF2 training set.

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    Figure 4

    Figure 4. PDD for SARS-CoV-2 spike protein inhibitors (filled bars) and inactive compounds (empty bars) obtained using DF2.

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    Figure 5

    Figure 5. SPI descriptor values for all macrolides under study.

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    Figure 6

    Figure 6. Selected antibiotics protect from the cytopathic effect of SARS-CoV-2 infection. Vero-E6 cells were inoculated at MOI 0.001 with SARS-CoV-2 in the absence or presence of increasing doses of the compounds. (A and B) Seventy-two hours later, cells were fixed and stained with crystal violet, and the percentage of remaining biomass was estimated per well. (A) Image of a representative experiment showing protection from SARS-CoV-2 infection. (B) Quantitation of the data shown in A. Data are shown as the average and standard deviation of three biological replicates and are expressed as the relative protection in the presence of the compound as compared with the vehicle (DMSO). (C) Toxicity of compounds was determined by quantitation of crystal violet staining of uninfected Vero-E6 cells that were treated in parallel as described in panel A. Data are shown as the average and standard deviation (Mean; SD; n = 3).

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    Figure 7

    Figure 7. Selected antibiotics display antiviral activity against SARS-CoV-2 infection. Vero-E6 cells were inoculated at MOI 0.001 with SARS-CoV-2 in the presence of nontoxic concentrations of azithromycin (100 μM), clarithromycin (100 μM), or lexithromycin (50 μM). Forty-eight hours postinfection, supernatants were collected, and the infectivity titers were determined. Data are expressed as average and standard deviation of the TCID50 values per ml of supernatant obtained in control and compound-treated cells. The lower LoD of the assay is represented by the discontinued gray line. Note that virus was undetectable in compound-treated conditions, despite the fact that supernatants were diluted below the effective concentrations during the titration assay.

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    Figure 8

    Figure 8. Selected antibiotics reduce intracellular SARS-CoV-2 RNA accumulation. Vero-E6 cells were inoculated at MOI 5 with SARS-CoV-2 in the presence or absence of the indicated compound concentrations. (A) Diagram explaining the experimental setup used in the experiment. Cells were treated with the compounds either at the time of virus inoculation (black bar) or 2 h thereafter (white bar), and compounds were maintained until the end of the experiment. At 6 h postinfection, cell lysates were prepared, and the RNA content was analyzed as described in the Materials and Methods section. (B) Relative intracellular SARS-CoV-2 RNA quantitation in control and compound-treated samples. Data are expressed as the average and standard deviation of biological triplicates. Note that the antiviral effect of compounds is greatly reduced when they are added after virus entry has occurred (white bars) compared to when they are added together with the virus (black bars).

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    Figure 9

    Figure 9. Selected antibiotics inhibit SARS-CoV-2 entry into target cells. Vero-E6 cell monolayers were inoculated with retroviral vectors pseudotyped with SARS-CoV-2 spike protein (SARS2pp) or VSV envelope glycoprotein (VSVpp) in the absence or presence of increasing doses of the compounds (i.e., 50 and 100 μM for azithromycin and clarithromycin and 12.5 and 25 μM for lexithromycin). Forty-eight hours postinoculation, luciferase activity was determined in whole-cell lysates. Data are expressed as relative luciferase activity values obtained in control and compound-treated cells. Data are shown as the average and standard deviation of three biological replicates.

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  • References

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      Remdesivir for the treatment of Covid-19 - Final Report
      Beigel, J. H.; Tomashek, K. M.; Dodd, L. E.; Mehta, A. K.; Zingman, B. S.; Kalil, A. C.; Hohmann, E.; Chu, H. Y.; Luetkemeyer, A.; Kline, S.; de Castilla, D. Lopez; Finberg, R. W.; Dierberg, K.; Tapson, V.; Hsieh, L.; Patterson, T. F.; Paredes, R.; Sweeney, D. A.; Short, W. R.; Touloumi, G.; Lye, D. C.; Ohmagari, N.; Oh, M.; Ruiz-Palacios, G. M.; Benfield, T.; Fatkenheuer, G.; Kortepeter, M. G.; Atmar, R. L.; Creech, C. B.; Lundgren, J.; Babiker, A. G.; Pett, S.; Neaton, J. D.; Burgess, T. H.; Bonnett, T.; Green, M.; Makowski, M.; Osinusi, A.; Nayak, S.; Lane, H. C.
      New England Journal of Medicine (2020), 383 (19), 1813-1826CODEN: NEJMAG; ISSN:1533-4406. (Massachusetts Medical Society)
      Background: Although several therapeutic agents have been evaluated for the treatment of coronavirus disease 2019 (Covid-19), no antiviral agents have yet been shown to be efficacious. methods the authors conducted a double-blind, randomized, placebo-controlled trial of i.v. remdesivir in adults who were hospitalized with Covid-19 and had evidence of lower respiratory tract infection. Patients were randomly assigned to receive either remdesivir (200 mg loading dose on day 1, followed by 100 mg daily for up to 9 addnl. days) or placebo for up to 10 days. The primary outcome was the time to recovery, defined by either discharge from the hospital or hospitalization for infection-control purposes only. results A total of 1062 patients underwent randomization (with 541 assigned to remdesivir and 521 to placebo). Those who received remdesivir had a median recovery time of 10 days (95% confidence interval [CI], 9 to 11), as compared with 15 days (95% CI, 13 to 18) among those who received placebo (rate ratio for recovery, 1.29; 95% CI, 1.12 to 1.49; P<0.001, by a log-rank test). In an anal. that used a proportional-odds model with an eight-category ordinal scale, the patients who received remdesivir were found to be more likely than those who received placebo to have clin. improvement at day 15 (odds ratio, 1.5; 95% CI, 1.2 to 1.9, after adjustment for actual disease severity). The Kaplan-Meier ests. of mortality were 6.7% with remdesivir and 11.9% with placebo by day 15 and 11.4% with remdesivir and 15.2% with placebo by day 29 (hazard ratio, 0.73; 95% CI, 0.52 to 1.03). Serious adverse events were reported in 131 of the 532 patients who received remdesivir (24.6%) and in 163 of the 516 patients who received placebo (31.6%). conclusions the authors' data show that remdesivir was superior to placebo in shortening the time to recovery in adults who were hospitalized with Covid-19 and had evidence of lower respiratory tract infection.
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    5. 5
      Poddighe, D.; Aljofan, M. Clinical evidences on the antiviral properties of macrolide antibiotics in the COVID-19 era and beyond. Antivir. Chem. Chemother. 2020, 28, 204020662096171  DOI: 10.1177/2040206620961712
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    6. 6
      Amsden, G. W. Anti-inflammatory effects of macrolides—an underappreciated benefit in the treatment of community-acquired respiratory tract infections and chronic inflammatory pulmonary conditions?. J. Antimicrob. Chemother. 2005, 55, 10– 21,  DOI: 10.1093/jac/dkh519
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      Anti-inflammatory effects of macrolides-an underappreciated benefit in the treatment of community-acquired respiratory tract infections and chronic inflammatory pulmonary conditions?
      Amsden, G. W.
      Journal of Antimicrobial Chemotherapy (2005), 55 (1), 10-21CODEN: JACHDX; ISSN:0305-7453. (Oxford University Press)
      A review. It was recognized for more than 20 years that the macrolides have immunomodulatory effects that are beneficial for those suffering from chronic pulmonary inflammatory syndromes, such as diffuse panbronchiolitis, cystic fibrosis, asthma and bronchiectasis. The macrolides have consistently been assocd. with decreased length of stay and mortality when used alone or in combination with β-lactam antibiotics. This effect can be demonstrated against combinations consisting of β-lactams and other antibiotics active against 'atypical chest pathogens' when treating community-acquired pneumonia (CAP) in hospitalized patients. As such, it appears that the macrolides' effects in CAP patients are more than just antibacterial in nature. This review aims: to give the reader information on the background areas described, as well as related areas; to review the CAP benefits with macrolides and how they may be related to the immunomodulatory properties they demonstrate, albeit in a shorter period of time than previously demonstrated with chronic pulmonary disorders; to use ex vivo data to support these extrapolations. A literature search using Medline was conducted from 1966 onwards, searching for articles with relevant key words such as macrolide, diffuse panbronchiolitis, community-acquired pneumonia, biofilm, immunomodulation, cystic fibrosis, erythromycin, clarithromycin, roxithromycin and azithromycin, bronchiectasis and asthma. When appropriate, addnl. refs. were found from the bibliogs. of identified papers of interest. Any relevant scientific conference proceedings or medical texts were checked when necessary. Research into macrolide immunomodulation for chronic pulmonary disorders demonstrates consistent pos. effects, although of types other than seen with diffuse panbronchiolitis. These effects, together with their inhibitory activity on biofilms, have the potential to make them a useful option. The benefits for CAP are consistent, and higher when a macrolide is given with another atypical agent than if the other atypical agent is given alone, suggesting a non-antibacterial benefit. Recent research of the immunomodulatory properties of azithromycin imply that azithromycin may have a previously unknown short-term biphasic effect on inflammation modulation: enhancement of host defense mechanisms shortly after initial administration followed by curtailment of local infection/inflammation in the following period. Addnl. in vivo research is needed prior to developing any firm conclusions.
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    7. 7
      Kanoh, S.; Rubin, B. K. Mechanisms of action and clinical application of macrolides as immunomodulatory medications. Clin. Microbiol. Rev. 2010, 23, 590– 615,  DOI: 10.1128/CMR.00078-09
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      Mechanisms of action and clinical application of macrolides as immunomodulatory medications
      Kanoh, Soichiro; Rubin, Bruce K.
      Clinical Microbiology Reviews (2010), 23 (3), 590-615CODEN: CMIREX; ISSN:0893-8512. (American Society for Microbiology)
      A review. Macrolides have diverse biol. activities and an ability to modulate inflammation and immunity in eukaryotes without affecting homeostatic immunity. These properties have led to their long-term use in treating neutrophil-dominated inflammation in diffuse panbronchiolitis, bronchiectasis, rhinosinusitis, and cystic fibrosis. These immunomodulatory activities appear to be polymodal, but evidence suggests that many of these effects are due to inhibition of extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation and nuclear factor kappa B (NF-κB) activation. Macrolides accumulate within cells, suggesting that they may assoc. with receptors or carriers responsible for the regulation of cell cycle and immunity. A concern is that long-term use of macrolides increases the emergence of antimicrobial resistance. Non-antimicrobial macrolides are now in development as potential immunomodulatory therapies.
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    8. 8
      Min, J.-Y.; Jang, Y. J. Macrolide therapy in respiratory viral infections. Mediators Inflamm. 2012, 2012, 649570  DOI: 10.1155/2012/649570
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      8
      Macrolide therapy in respiratory viral infections
      Min Jin-Young; Jang Yong Ju
      Mediators of inflammation (2012), 2012 (), 649570 ISSN:.
      BACKGROUND: Macrolides have received considerable attention for their anti-inflammatory and immunomodulatory actions beyond the antibacterial effect. These two properties may ensure some efficacy in a wide spectrum of respiratory viral infections. We aimed to summarize the properties of macrolides and their efficacy in a range of respiratory viral infection. METHODS: A search of electronic journal articles through PubMed was performed using combinations of the following keywords including macrolides and respiratory viral infection. RESULTS: Both in vitro and in vivo studies have provided evidence of their efficacy in respiratory viral infections including rhinovirus (RV), respiratory syncytial virus (RSV), and influenza virus. Much data showed that macrolides reduced viral titers of RV ICAM-1, which is the receptor for RV, and RV infection-induced cytokines including IL-1β, IL-6, IL-8, and TNF-α. Macrolides also reduced the release of proinflammatory cytokines which were induced by RSV infection, viral titers, RNA of RSV replication, and the susceptibility to RSV infection partly through the reduced expression of activated RhoA which is an RSV receptor. Similar effects of macrolides on the influenza virus infection and augmentation of the IL-12 by macrolides which is essential in reducing virus yield were revealed. CONCLUSION: This paper provides an overview on the properties of macrolides and their efficacy in various respiratory diseases.
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    9. 9
      Lin, S.-J.; Kuo, M.-L.; Hsiao, H.-S.; Lee, P.-T. Azithromycin modulates immune response of human monocyte-derived dendritic cells and CD4 T cells. Int. Immunopharmacol. 2016, 40, 318– 326,  DOI: 10.1016/j.intimp.2016.09.012
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      9
      Azithromycin modulates immune response of human monocyte-derived dendritic cells and Cd4+ T cells
      Lin, Syh-Jae; Kuo, Ming-Ling; Hsiao, Hsiu-Shan; Lee, Pei-Tzu
      International Immunopharmacology (2016), 40 (), 318-326CODEN: IINMBA; ISSN:1567-5769. (Elsevier B.V.)
      Azithromycin (AZM) is a macrolide antibiotic that exhibits anti-inflammatory activity aside from its antimicrobial effect, a feature that may ameliorate certain inflammatory disorders and prevent graft-vs.-host disease in patients receiving stem cell transplantation. In the present study, we investigated the ability of AZM to influence the function of human monocyte-derived dendritic cells (DCs) and CD4+ T cells. We found that AZM down-regulated CD80, CD86, and HLA-DR expression in lipopolysaccharide (LPS)-stimulated DCs and suppressed interleukin (IL)-6, IL-10, IL-12, and tumor necrosis factor-alpha prodn. in these cells. In addn., AZM increased endocytosis and/or expression of Toll-like receptor (TLR)2, TLR4, and TLR9 in DCs and suppressed anti-CD3/CD28-induced CD4+ T cell proliferation and interferon-gamma prodn., an effect that was synergistic with dexamethasone. Finally, AZM suppressed DC-induced allogeneic T cell proliferation and cytokine prodn. Our study demonstrates that AZM modulates DC and CD4+ T cell function and may be of therapeutic benefit in various inflammatory disorders.
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    10. 10
      Tahan, F.; Ozcan, A.; Koc, N. Clarithromycin in the treatment of RSV bronchiolitis: a double-blind, randomised, placebo-controlled trial. Eur. Respir. J. 2007, 29, 91– 97,  DOI: 10.1183/09031936.00029206
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      10
      Clarithromycin in the treatment of RSV bronchiolitis: a double-blind, randomized, placebo-controlled trial
      Tahan, F.; Ozcan, A.; Koc, N.
      European Respiratory Journal (2007), 29 (1), 91-97CODEN: ERJOEI; ISSN:0903-1936. (European Respiratory Society)
      Respiratory syncytial virus (RSV) bronchiolitis is the most common lower respiratory tract infection in infancy. To date, there is no effective therapy for RSV bronchiolitis. In order to investigate the efficacy of clarithromycin in the treatment of RSV bronchiolitis, the present authors conducted a randomized, double-blind, placebo-controlled trial comparing clarithromycin with placebo in 21 infants with a diagnosis of RSV bronchiolitis. The infants were randomized to receive clarithromycin or placebo daily for 3 wk. Levels of interleukin (IL)-4, IL-8, eotaxin, and interferon-γ were detd. in plasma, before and after treatment, using ELISA. Six months after treatment, parents were surveyed as to whether their child had experienced wheezing within the previous 6 mo. Treatment with clarithromycin was assocd. with a statistically significant redn. in the length of hospital stay, the duration of need for supplemental oxygen and the need for β2-agonist treatment. There were significant decreases in plasma IL-4, IL-8 and eotaxin levels after 3 wk of treatment with clarithromycin. Readmission to the hospital within 6 mo after discharge was significantly lower in the clarithromycin group. In conclusion, clarithromycin has statistically significant effects on the clin. and lab. findings in respiratory syncytial virus bronchiolitis. Therefore, clarithromycin treatment may be helpful in reducing the short-term effects of respiratory syncytial virus bronchiolitis.
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    11. 11
      Suzuki, T.; Yamaya, M.; Sekizawa, K.; Hosoda, M.; Yamada, N.; Ishizuka, S.; Yoshino, A.; Yasuda, H.; Takahashi, H.; Nishimura, H. Erythromycin inhibits rhinovirus infection in cultured human tracheal epithelial cells. Am. J. Respir. Crit. Care Med. 2002, 165, 1113– 1118,  DOI: 10.1164/ajrccm.165.8.2103094
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      11
      Erythromycin inhibits rhinovirus infection in cultured human tracheal epithelial cells
      Suzuki Tomoko; Yamaya Mutsuo; Sekizawa Kiyohisa; Hosoda Masayoshi; Yamada Norihiro; Ishizuka Satoshi; Yoshino Akiko; Yasuda Hiroyasu; Takahashi Hidenori; Nishimura Hidekazu; Sasaki Hidetada
      American journal of respiratory and critical care medicine (2002), 165 (8), 1113-8 ISSN:1073-449X.
      To examine the effects of erythromycin on rhinovirus (RV) infection in airway epithelium, primary cultures of human tracheal epithelial cells were infected with the RV major subgroup, RV14, and the minor subgroup, RV2. Infection was confirmed by increases in viral RNA of the infected cells and viral titers of the supernatants. RV14 upregulated the expression of the mRNA and protein of intercellular adhesion molecule-1 (ICAM-1), the major RV receptor, and it increased the cytokine production. Erythromycin reduced the supernatant RV14 titers, RV14 RNA, the susceptibility to RV14 infection, and the production of ICAM-1 and cytokines. Erythromycin also reduced the supernatant RV2 titers, RV2 RNA, the susceptibility to RV2 infection, and cytokine production, although the inhibitory effects of erythromycin on the expression of the low-density lipoprotein receptor, the minor RV receptor, were small. Erythromycin reduced the nuclear factor-kappaB activation by RV14 and decreased the number of acidic endosomes in the epithelial cells. These results suggest that erythromycin inhibits infection by the major RV subgroup by reducing ICAM-1 and infection by both RV subgroups by blocking the RV RNA entry into the endosomes. Erythromycin may also modulate airway inflammation by reducing the production of proinflammatory cytokines and ICAM-1 induced by RV infection.
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    12. 12
      Jang, Y. J.; Kwon, H. J.; Lee, B. J. Effect of clarithromycin on rhinovirus-16 infection in A549 cells. Eur. Respir. J. 2006, 27, 12– 19,  DOI: 10.1183/09031936.06.00008005
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      12
      Effect of clarithromycin on rhinovirus-16 infection in A549 cells
      Jang, Y. J.; Kwon, H.-J.; Lee, B.-J.
      European Respiratory Journal (2006), 27 (1), 12-19CODEN: ERJOEI; ISSN:0903-1936. (European Respiratory Society)
      Clarithromycin (CM) has been found to inhibit the prodn. of the intercellular adhesion mol. (ICAM)-1 and the secretion of interleukin (IL)-6 and IL-8, which may have beneficial effects on the pathophysiol. changes related to rhinovirus (RV) infection. The effect of CM on RV infection in A549 cells was therefore investigated. Cells were pre-treated with 1, 10 or 100 μM CM, either starting 3 days before infection and continuing thereafter, or by addn. at the time of infection. RV titer, as measured by culture on Medical Research Council 5 cells, was reduced by CM, with the degree of redn. being greater when CM was added 3 days before infection than when it was added at the time of infection. CM treatment inhibited the RV-induced increase in ICAM-1 mRNA and protein, as well as the RV-induced secretion of IL-1β, IL-6, and IL-8. These effects were greater in cells treated with 10 μM than in those treated with 100 μM CM, and the max. effect was obsd. 3 days after viral infection. In contrast, secretion of IL-8 was not inhibited significantly when CM was added at the time of viral infection. The findings of this study suggest that, in A549 cells, clarithromycin inhibits the induction of intercellular adhesion mol.-1 expression, cytokine elaboration, and viral infection.
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    13. 13
      Yamaya, M.; Shinya, K.; Hatachi, Y.; Kubo, H.; Asada, M.; Yasuda, H.; Nishimura, H.; Nagatomi, R. Clarithromycin inhibits type a seasonal influenza virus infection in human airway epithelial cells. J. Pharmacol. Exp. Ther. 2010, 333, 81– 90,  DOI: 10.1124/jpet.109.162149
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      13
      Clarithromycin inhibits type A seasonal influenza virus infection in human airway epithelial cells
      Yamaya, Mutsuo; Shinya, Kyoko; Hatachi, Yukimasa; Kubo, Hiroshi; Asada, Masanori; Yasuda, Hiroyasu; Nishimura, Hidekazu; Nagatomi, Ryoichi
      Journal of Pharmacology and Experimental Therapeutics (2010), 333 (1), 81-90CODEN: JPETAB; ISSN:0022-3565. (American Society for Pharmacology and Experimental Therapeutics)
      Human influenza viruses attach to sialic acid with an α2,6 linkage (SAα2,6Gal) on the airway epithelial cells, and the entry of the viruses into the cells and uncoating of the viruses require low pH of endosomes. Bafilomycin A1, a macrolide antibiotic and a specific inhibitor of vacuolar H+-ATPase, inhibits growth of type A and type B human influenza viruses in Madin-Darby canine kidney cells. However, the inhibitory effects of clin. used macrolide antibiotics on influenza virus infection in human airways have not been studied. To examine the effects of clarithromycin on seasonal human influenza virus infection, cultured human tracheal epithelial cells were infected with type A influenza virus (H3N2). Influenza virus infection increased viral titers and the content of cytokines, including interleukin (IL)-1β and IL-6, in supernatant fluids, and viral RNA in the cells. Clarithromycin reduced viral titers and the content of cytokines in supernatant fluids, viral RNA in the cells, and the susceptibility to virus infection. Clarithromycin reduced the expression of SAα2,6Gal, a receptor for human influenza virus, on the mucosal surface of human tracheae, and the no. and fluorescence intensity of acidic endosomes in the cells from which viral ribonucleoproteins enter into the cytoplasm. Furthermore, clarithromycin reduced nuclear factor-κB (NF-κB) proteins, including p50 and p65, in the nuclear exts. These results suggest that clarithromycin may inhibit seasonal human influenza virus infection by reducing SAα2,6Gal partly through the inhibition of NF-κB, and increasing pH in endosomes in airway epithelial cells. Clarithromycin may modulate airway inflammation in influenza virus infection.
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    14. 14
      Lee, N.; Wong, C.; Chan, M. C.; Yeung, E. S.; Tam, W. W.; Tsang, O. T.; Choi, K.; Chan, P. K.; Kwok, A.; Lui, G. C. Anti-inflammatory effects of adjunctive macrolide treatment in adults hospitalized with influenza: a randomized controlled trial. Antiviral Res. 2017, 144, 48– 56,  DOI: 10.1016/j.antiviral.2017.05.008
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      14
      Anti-inflammatory effects of adjunctive macrolide treatment in adults hospitalized with influenza: A randomized controlled trial
      Lee, Nelson; Wong, Chun-Kwok; Chan, Martin C. W.; Yeung, Esther S. L.; Tam, Wilson W. S.; Tsang, Owen T. Y.; Choi, Kin-Wing; Chan, Paul K. S.; Kwok, Angela; Lui, Grace C. Y.; Leung, Wai-Shing; Yung, Irene M. H.; Wong, Rity Y. K.; Cheung, Catherine S. K.; Hui, David S. C.
      Antiviral Research (2017), 144 (), 48-56CODEN: ARSRDR; ISSN:0166-3542. (Elsevier B.V.)
      - Macrolides can ameliorate inflammation in respiratory diseases, providing clin. benefits. Data in influenza is lacking.- A randomized, open-label, multicenter trial among adults hospitalized for lab.-confirmed influenza was conducted. Study treatments of oseltamivir and azithromycin (500 mg/day), or oseltamivir alone, both for 5 days, were allocated at 1:1 ratio. The primary outcome was plasma cytokine/chemokine concn. change over time (Day 0-10); secondary outcomes were viral load and symptom score changes. Generalized Estg. Equation (GEE) models were used to analyze longitudinal data.- Fifty patients were randomized to the oseltamivir-azithromycin or oseltamivir groups, with comparable baseline characteristics (age, 57 ± 18 years; A/H3N2, 70%), complications (72%), and viral load. Pro-inflammatory cytokines IL-6 (GEE: β -0.037, 95%CI-0.067,-0.007, P = 0.016; redn. from baseline -83.4% vs -59.5%), CXCL8/IL-8 (β -0.018, 95%CI-0.037,0.000, P = 0.056; -80.5% vs -58.0%), IL-17 (β -0.064, 95%CI-0.117,-0.012, P = 0.015; -74.0% vs -34.3%), CXCL9/MIG (β -0.010, 95%CI-0.020,0.000, P = 0.043; -71.3% vs -56.0%), sTNFR-1, IL-18, and CRP declined faster in the oseltamivir-azithromycin group. There was a trend toward faster symptom resoln. (β -0.463, 95%CI-1.297,0.371). Viral RNA decline (P = 0.777) and culture-negativity rates were unaffected. Addnl. ex vivo studies confirmed reduced induction of IL-6 (P = 0.017) and CXCL8/IL-8 (P = 0.005) with azithromycin.- We found significant anti-inflammatory effects with adjunctive macrolide treatment in adults with severe influenza infections. Virus control was unimpaired. Clin. benefits of a macrolide-contg. regimen deserve further study.[ClinicalTrials.gov NCT01779570].
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    15. 15
      Bermejo-Martin, J. F.; Kelvin, D. J.; Eiros, J. M.; Castrodeza, J.; De Lejarazu, R. O. Macrolides for the treatment of severe respiratory illness caused by novel H1N1 swine influenza viral strains. J. Infect. Dev. Ctries. 2009, 3, 159– 161,  DOI: 10.3855/jidc.18
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      15
      Macrolides for the treatment of severe respiratory illness caused by novel H1N1 swine influenza viral strains
      Bermejo-Martin, Jesus F.; Kelvin, David J.; Eiros, Jose Maria; Castrodeza, Javier; de Lejarazu, Raul Ortiz
      Journal of Infection in Developing Countries (2009), 3 (3), 159-161CODEN: JIDCB9; ISSN:1972-2680. (OLoEP)
      A review. This paper presents the utilization of macrolides in the treatment of severe disease caused by the novel H1N1 swine flu reassortment influenza viruses. It has been proposed that macrolides be used in combination with antivirals, in order to diminish the systemic inflammatory response leading to pneumonia and fatal outcome. Macrolides are easy accessible: they are used in the hospitals of both developed and developing countries to treat bacterial infection; they are relatively cheap; and they show a good toxicity profile. Administration could be employed on the basis of a clin. score including high fever, chest X-ray images and O2 satn. as predictors for disease outcome.
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    16. 16
      Lendermon, E. A.; Coon, T. A.; Bednash, J. S.; Weathington, N. M.; McDyer, J. F.; Mallampalli, R. K. Azithromycin decreases NALP3 mRNA stability in monocytes to limit inflammasome-dependent inflammation. Respir. Res. 2017, 18, 1– 8,  DOI: 10.1186/s12931-017-0608-8
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      There is no corresponding record for this reference.
    17. 17
      Gautret, P.; Lagier, J.; Parola, P.; Meddeb, L.; Mailhe, M.; Doudier, B.; Courjon, J.; Giordanengo, V.; Vieira, V. E.; Dupont, H. T. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Int. J. Antimicrob. Agents 2020, 56, 105949  DOI: 10.1016/j.ijantimicag.2020.105949
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      17
      Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial
      Gautret, Philippe; Lagier, Jean-Christophe; Parola, Philippe; Hoang, Van Thuan; Meddeb, Line; Mailhe, Morgane; Doudier, Barbara; Courjon, Johan; Giordanengo, Valerie; Vieira, Vera Esteves; Tissot Dupont, Herve; Honore, Stephane; Colson, Philippe; Chabriere, Eric; La Scola, Bernard; Rolain, Jean-Marc; Brouqui, Philippe; Raoult, Didier
      International Journal of Antimicrobial Agents (2020), 56 (1), 105949CODEN: IAAGEA; ISSN:0924-8579. (Elsevier B.V.)
      Background: Chloroquine and hydroxychloroquine have been found to be efficient on SARS-CoV-2, and reported to be efficient in Chinese COV-19 patients. We evaluate the effect of hydroxychloroquine on respiratory viral loads. Patients and Methods: French Confirmed COVID-19 patients were included in a single arm protocol from early March to March 16th, to receive 600mg of hydroxychloroquine daily and their viral load in nasopharyngeal swabs was tested daily in a hospital setting. Depending on their clin. presentation, azithromycin was added to the treatment. Untreated patients from another center and cases refusing the protocol were included as neg. controls. Presence and absence of virus at Day6-post inclusion was considered the end point. Results: Six patients were asymptomatic, 22 had upper respiratory tract infection symptoms and eight had lower respiratory tract infection symptoms. Twenty cases were treated in this study and showed a significant redn. of the viral carriage at D6-post inclusion compared to controls, and much lower av. carrying duration than reported in the literature for untreated patients. Azithromycin added to hydroxychloroquine was significantly more efficient for virus elimination. Conclusions: Despite its small sample size, our survey shows that hydroxychloroquine treatment is significantly assocd. with viral load redn./disappearance in COVID-19 patients and its effect is reinforced by azithromycin.
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      Gautret, P.; Lagier, J.; Parola, P.; Meddeb, L.; Sevestre, J.; Mailhe, M.; Doudier, B.; Aubry, C.; Amrane, S.; Seng, P. Clinical and microbiological effect of a combination of hydroxychloroquine and azithromycin in 80 COVID-19 patients with at least a six-day follow up: a pilot observational study. Travel Med.Infect. Dis. 2020, 34, 101663  DOI: 10.1016/j.tmaid.2020.101663
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      18
      Clinical and microbiological effect of a combination of hydroxychloroquine and azithromycin in 80 COVID-19 patients with at least a six-day follow up: A pilot observational study
      Gautret Philippe; Parola Philippe; Eldin Carole; Fournier Pierre Edouard; Lagier Jean-Christophe; Tissot-Dupont Herve Tissot; Stein Andreas; Million Matthieu; Colson Philippe; La Scola Bernard; Drancourt Michel; Rolain Jean-Marc; Brouqui Philippe; Hoang Van Thuan; Meddeb Line; Sevestre Jacques; Mailhe Morgane; Doudier Barbara; Aubry Camille; Amrane Sophie; Seng Piseth; Hocquart Marie; Vieira Vera Esteves; Finance Julie; Honore Stephane; Veit Veronique; Jacquier Alexis; Deharo Jean-Claude; Raoult Didier
      Travel medicine and infectious disease (2020), 34 (), 101663 ISSN:.
      BACKGROUND: We need an effective treatment to cure COVID-19 patients and to decrease virus carriage duration. METHODS: We conducted an uncontrolled, non-comparative, observational study in a cohort of 80 relatively mildly infected inpatients treated with a combination of hydroxychloroquine and azithromycin over a period of at least three days, with three main measurements: clinical outcome, contagiousness as assessed by PCR and culture, and length of stay in infectious disease unit (IDU). RESULTS: All patients improved clinically except one 86 year-old patient who died, and one 74 year-old patient still in intensive care. A rapid fall of nasopharyngeal viral load was noted, with 83% negative at Day7, and 93% at Day8. Virus cultures from patient respiratory samples were negative in 97.5% of patients at Day5. Consequently patients were able to be rapidly discharged from IDU with a mean length of stay of five days. CONCLUSION: We believe there is urgency to evaluate the effectiveness of this potentially-life saving therapeutic strategy at a larger scale, both to treat and cure patients at an early stage before irreversible severe respiratory complications take hold and to decrease duration of carriage and avoid the spread of the disease. Furthermore, the cost of treatment is negligible.
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    19. 19
      Cavalcanti, A. B.; Zampieri, F. G.; Rosa, R. G.; Azevedo, L. C.; Veiga, V. C.; Avezum, A.; Damiani, L. P.; Marcadenti, A.; Kawano-Dourado, L.; Lisboa, T. Hydroxychloroquine with or without Azithromycin in Mild-to-Moderate Covid-19. N. Engl. J. Med. 2020, 383, 2041– 2052,  DOI: 10.1056/NEJMoa2019014
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      19
      Hydroxychloroquine with or without azithromycin in mild-to-moderate Covid-19
      Cavalcanti, A. B.; Zampieri, F. G.; Rosa, R. G.; Azevedo, L. C. P.; Veiga, V. C.; Avezum, A.; Damiani, L. P.; Marcadenti, A.; Kawano-Dourado, L.; Lisboa, T.; Junqueira, D. L. M.; de Barros e Silva, P. G. M.; Tramujas, L.; Abreu-Silva, E. O.; Laranjeira, L. N.; Soares, A. T.; Echenique, L. S.; Pereira, A. J.; Freitas, F. G. R.; Gebara, O. C. E.; Dantas, V. C. S.; Furtado, R. H. M.; Milan, E. P.; Golin, N. A.; Cardoso, F. F.; Maia, I. S.; Filho, C. R. Hoffmann; Kormann, A. P. M.; Amazonas, R. B.; Bocchi de Oliveira, M. F.; Serpa-Neto, A.; Falavigna, M.; Lopes, R. D.; Machado, F. R.; Berwanger, O.
      New England Journal of Medicine (2020), 383 (21), 2041-2052CODEN: NEJMAG; ISSN:1533-4406. (Massachusetts Medical Society)
      Hydroxychloroquine and azithromycin have been used to treat patients with coronavirus disease 2019 (Covid-19). However, evidence on the safety and efficacy of these therapies is limited. We conducted a multicenter, randomized, open-label, three-group, controlled trial involving hospitalized patients with suspected or confirmed Covid-19 who were receiving either no supplemental oxygen or a max. of 4 L per min of supplemental oxygen. Patients were randomly assigned in a 1:1:1 ratio to receive std. care, std. care plus hydroxychloroquine at a dose of 400 mg twice daily, or std. care plus hydroxychloroquine at a dose of 400 mg twice daily plus azithromycin at a dose of 500 mg once daily for 7 days. The primary outcome was clin. status at 15 days as assessed with the use of a seven-level ordinal scale (with levels ranging from one to seven and higher scores indicating a worse condition) in the modified intention-to-treat population (patients with a confirmed diagnosis of Covid-19). Safety was also assessed. A total of 667 patients underwent randomization; 504 patients had confirmed Covid-19 and were included in the modified intention-to-treat anal. As compared with std. care, the proportional odds of having a higher score on the seven-point ordinal scale at 15 days was not affected by either hydroxychloroquine alone (odds ratio, 1.21; 95% confidence interval [CI], 0.69 to 2.11; P = 1.00) or hydroxychloroquine plus azithromycin (odds ratio, 0.99; 95% CI, 0.57 to 1.73; P = 1.00). Prolongation of the cor. QT interval and elevation of liver-enzyme levels were more frequent in patients receiving hydroxychloroquine, alone or with azithromycin, than in those who were not receiving either agent. Among patients hospitalized with mild-to-moderate Covid-19, the use of hydroxychloroquine, alone or with azithromycin, did not improve clin. status at 15 days as compared with std. care.
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    20. 20
      Rosenberg, E. S.; Dufort, E. M.; Udo, T.; Wilberschied, L. A.; Kumar, J.; Tesoriero, J.; Weinberg, P.; Kirkwood, J.; Muse, A.; DeHovitz, J. Association of treatment with hydroxychloroquine or azithromycin with in-hospital mortality in patients with COVID-19 in New York State. JAMA 2020, 323, 2493– 2502,  DOI: 10.1001/jama.2020.8630
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      Association of treatment with hydroxychloroquine or azithromycin with in-hospital mortality in patients with COVID-19 in New York State
      Rosenberg, Eli S.; Dufort, Elizabeth M.; Udo, Tomoko; Wilberschied, Larissa A.; Kumar, Jessica; Tesoriero, James; Weinberg, Patti; Kirkwood, James; Muse, Alison; DeHovitz, Jack; Blog, Debra S.; Hutton, Brad; Holtgrave, David R.; Zucker, Howard A.
      JAMA, the Journal of the American Medical Association (2020), 323 (24), 2493-2502CODEN: JAMAAP; ISSN:1538-3598. (American Medical Association)
      Hydroxychloroquine, with or without azithromycin, has been considered as a possible therapeutic agent for patients with coronavirus disease 2019 (COVID-19). However, there are limited data on efficacy and assocd. adverse events. To describe the assocn. between use of hydroxychloroquine, with or without azithromycin, and clin. outcomes among hospital inpatients diagnosed with COVID-19. Retrospective multicenter cohort study of patients from a random sample of all admitted patients with lab.-confirmed COVID-19 in 25 hospitals, representing 88.2% of patients with COVID-19 in the New York metropolitan region. Eligible patients were admitted for at least 24 h between March 15 and 28, 2020. Medications, preexisting conditions, clin. measures on admission, outcomes, and adverse events were abstracted from medical records. The date of final follow-up was Apr. 24, 2020. exposures Receipt of both hydroxychloroquine and azithromycin, hydroxychloroquine alone, azithromycin alone, or neither. main outcomes and measures Primary outcome was in-hospital mortality. Secondary outcomes were cardiac arrest and abnormal ECG findings (arrhythmia or QT prolongation). Among 1438 hospitalized patients with a diagnosis of COVID-19 (858 [59.7%] male, median age, 63 years), those receiving hydroxychloroquine, azithromycin, or both were more likely than those not receiving either drug to have diabetes, respiratory rate >22/min, abnormal chest imaging findings, O2 satn. lower than 90%, and aspartate aminotransferase greater than 40 U/L. Overall in-hospital mortality was 20.3% (95% CI, 18.2%-22.4%). The probability of death for patients receiving hydroxychloroquine + azithromycin was 189/735 (25.7% [95% CI, 22.3%-28.9%]), hydroxychloroquine alone, 54/271 (19.9% [95% CI, 15.2%-24.7%]), azithromycin alone, 21/211 (10.0% [95% CI, 5.9%-14.0%]), and neither drug, 28/221 (12.7% [95% CI, 8.3%-17.1%]). In adjusted Cox proportional hazards models, compared with patients receiving neither drug, there were no significant differences in mortality for patients receiving hydroxychloroquine + azithromycin (HR, 1.35 [95% CI, 0.76-2.40]), hydroxychloroquine alone (HR, 1.08 [95% CI, 0.63-1.85]), or azithromycin alone (HR, 0.56 [95% CI, 0.26-1.21]). In logistic models, compared with patients receiving neither drug cardiac arrest was significantly more likely in patients receiving hydroxychloroquine + azithromycin (adjusted OR, 2.13 [95% CI, 1.12-4.05]), but not hydroxychloroquine alone (adjusted OR, 1.91 [95% CI, 0.96-3.81]) or azithromycin alone (adjusted OR, 0.64 [95% CI, 0.27-1.56]),. In adjusted logistic regression models, there were no significant differences in the relative likelihood of abnormal ECG findings. conclusions and relevance Among patients hospitalized in metropolitan New York with COVID-19, treatment with hydroxychloroquine, azithromycin, or both, compared with neither treatment, was not significantly assocd. with differences in in-hospital mortality. However, the interpretation of these findings may be limited by the observational design.
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    21. 21
      Furtado, R. H. M.; Berwanger, O.; Fonseca, H. A.; Corrêa, T. D.; Ferraz, L. R.; Lapa, M. G.; Zampieri, F. G.; Veiga, V. C.; Azevedo, L. C.; Rosa, R. G. Azithromycin in addition to standard of care versus standard of care alone in the treatment of patients admitted to the hospital with severe COVID-19 in Brazil (COALITION II): a randomised clinical trial. Lancet 2020, 396, 959– 967,  DOI: 10.1016/S0140-6736(20)31862-6
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      21
      Azithromycin in addition to standard of care versus standard of care alone in the treatment of patients admitted to the hospital with severe COVID-19 in Brazil (COALITION II): a randomised clinical trial
      Furtado, Remo H. M.; Berwanger, Otavio; Fonseca, Henrique A.; Correa, Thiago D.; Ferraz, Leonardo R.; Lapa, Maura G.; Zampieri, Fernando G.; Veiga, Viviane C.; Azevedo, Luciano C. P.; Rosa, Regis G.; Lopes, Renato D.; Avezum, Alvaro; Manoel, Airton L. O.; Piza, Felipe M. T.; Martins, Priscilla A.; Lisboa, Thiago C.; Pereira, Adriano J.; Olivato, Guilherme B.; Dantas, Vicente C. S.; Milan, Eveline P.; Gebara, Otavio C. E.; Amazonas, Roberto B.; Oliveira, Monalisa B.; Soares, Ronaldo V. P.; Moia, Diogo D. F.; Piano, Luciana P. A.; Castilho, Kleber; Momesso, Roberta G. R. A. P.; Schettino, Guilherme P. P.; Rizzo, Luiz Vicente; Neto, Ary Serpa; Machado, Flavia R.; Cavalcanti, Alexandre B.
      Lancet (2020), 396 (10256), 959-967CODEN: LANCAO; ISSN:0140-6736. (Elsevier Ltd.)
      The efficacy and safety of azithromycin in the treatment of COVID-19 remain uncertain. We assessed whether adding azithromycin to std. of care, which included hydroxychloroquine, would improve clin. outcomes of patients admitted to the hospital with severe COVID-19. We did an open-label, randomised clin. trial at 57 centers in Brazil. We enrolled patients admitted to hospital with suspected or confirmed COVID-19 and at least one addnl. severity criteria as follows: use of oxygen supplementation of more than 4 L/min flow; use of high-flow nasal cannula; use of non-invasive mech. ventilation; or use of invasive mech. ventilation. Patients were randomly assigned (1:1) to azithromycin (500 mg via oral, nasogastric, or i.v. administration once daily for 10 days) plus std. of care or to std. of care without macrolides. All patients received hydroxychloroquine (400 mg twice daily for 10 days) because that was part of std. of care treatment in Brazil for patients with severe COVID-19. The primary outcome, assessed by an independent adjudication committee masked to treatment allocation, was clin. status at day 15 after randomisation, assessed by a six-point ordinal scale, with levels ranging from 1 to 6 and higher scores indicating a worse condition (with odds ratio [OR] greater than 1·00 favoring the control group). The primary outcome was assessed in all patients in the intention-to-treat (ITT) population who had severe acute respiratory syndrome coronavirus 2 infection confirmed by mol. or serol. testing before randomisation (ie, modified ITT [mITT] population). Safety was assessed in all patients according to which treatment they received, regardless of original group assignment. This trial was registered at ClinicalTrials.gov, NCT04321278.447 patients were enrolled from March 28 to May 19, 2020. COVID-19 was confirmed in 397 patients who constituted the mITT population, of whom 214 were assigned to the azithromycin group and 183 to the control group. In the mITT population, the primary endpoint was not significantly different between the azithromycin and control groups (OR 1·36 [95% CI 0·94-1·97], p=0·11). Rates of adverse events, including clin. relevant ventricular arrhythmias, resuscitated cardiac arrest, acute kidney failure, and cor. QT interval prolongation, were not significantly different between groups. In patients with severe COVID-19, adding azithromycin to std. of care treatment (which included hydroxychloroquine) did not improve clin. outcomes. Our findings do not support the routine use of azithromycin in combination with hydroxychloroquine in patients with severe COVID-19. COALITION COVID-19 Brazil and EMS.
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      Zanni, R.; Galvez-Llompart, M.; Garcia-Domenech, R.; Galvez, J. Latest advances in molecular topology applications for drug discovery. Expert Opin. Drug Discov. 2015, 10, 945– 957,  DOI: 10.1517/17460441.2015.1062751
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      Latest advances in molecular topology applications for drug discovery
      Zanni, Riccardo; Galvez-Llompart, Maria; Garcia-Domenech, Ramon; Galvez, Jorge
      Expert Opinion on Drug Discovery (2015), 10 (9), 945-957CODEN: EODDBX; ISSN:1746-0441. (Taylor & Francis Ltd.)
      Mol. topol. (MT) has emerged in recent years as a powerful approach for the in silico generation of new drugs. In the last decade, its application has become more and more popular among the leading research groups in the field of quant. structure-activity relationships (QSAR) and drug design. This has, in turn, contributed to the rapid development of new techniques and applications of MT in QSAR studies, as well as the introduction of new topol. indexes. This review collates the main innovative techniques in the field of MT and provides a description of the novel topol. indexes recently introduced, through an exhaustive recompilation of the most significant works carried out by the leading research groups in the field of drug design and discovery. The objective is to show the importance of MT methods combined with the effectiveness of the descriptors. Recent years have witnessed a remarkable rise in QSAR methods based on MT and its application to drug design. New methodologies have been introduced in the area such as QSAR multi-target, Markov networks or perturbation methods. Moreover, novel topol. indexes, such as Bourgas' descriptors and other new concepts as the deriv. of a graph or cliques capable to distinguish between conformers, have also been introduced. New drugs have also been discovered, including anticonvulsants, anineoplastics, antimalarials or antiallergics, just to name a few. In the authors' opinion, MT and QSAR have moved from an attractive possibility to representing a foundation stone in the process of drug discovery.
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      Sajib, A. Repurposing of Approved Drugs with Potential to Block SARS-CoV-2 Surface Glycoprotein Interaction with Host Receptor. Preprints 2020, 2020040369,  DOI: 10.20944/preprints202004.0369.v1
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      In vitro cytotoxicity tests for the prediction of acute toxicity in vivo
      Garle, M. J.; Fentem, J. H.; Fry, J. R.
      Toxicology in Vitro (1994), 8 (6), 1303-12CODEN: TIVIEQ; ISSN:0887-2333. (Elsevier)
      A review with many refs. The use of in vitro cytotoxicity tests for the prediction of acute toxicity in vivo was reviewed.
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      Kirst, H. A. Introduction to the macrolide antibiotics. In Macrolide antibiotics; Springer: 2002; 1– 13.
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      Tyteca, D.; Van Der Smissen, P.; Van Bambeke, F.; Leys, K.; Tulkens, P. M.; Courtoy, P. J.; Mingeot-Leclercq, M. Azithromycin, a lysosomotropic antibiotic, impairs fluid-phase pinocytosis in cultured fibroblasts. Eur. J. Cell Biol. 2001, 80, 466– 478,  DOI: 10.1078/0171-9335-00180
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      Azithromycin, a lysosomotropic antibiotic, impairs fluid-phase pinocytosis in cultured fibroblasts
      Tyteca, Donatienne; Van Der Smissen, Patrick; Van Bambeke, Francoise; Leys, Karin; Tulkens, Paul M.; Courtoy, Pierre J.; Mingeot-Leclercq, Marie-Paule
      European Journal of Cell Biology (2001), 80 (7), 466-478CODEN: EJCBDN; ISSN:0171-9335. (Urban & Fischer Verlag)
      The dicationic macrolide antibiotic azithromycin inhibited the uptake of horseradish peroxidase (HRP) by fluid-phase pinocytosis into fetal rat fibroblasts in a time- and concn.-dependent fashion without affecting its decay (regurgitation and/or degrdn.). The azithromycin effect was additive to that of nocodazole, known to impair endocytic uptake and transport of solutes along the endocytic pathway. Cytochem. (light and electron microscopy) showed a major redn. by azithromycin of the no. of HRP-labeled endocytic vesicles after 5 min (endosomes) and 2 h (lysosomes). Within 3 h of exposure, azithromycin also caused the appearance of large and light-lucent/electron-lucent vacuoles, most of which could be labeled by lucifer yellow when this tracer was added to culture prior to azithromycin exposure. Three days of treatment with azithromycin resulted in the accumulation of very large vesicles filled with pleiomorphic content, consistent with phospholipidosis. These vesicles were accessible to fluorescein-labeled bovine serum albumin and were intensively stained with filipin, indicating a mixed storage with cholesterol. The impairment of HRP pinocytosis directly correlated with the amt. of azithromycin accumulated by the cells, but not with the phospholipidosis induced by the drug. The proton ionophore monensin, which completely suppressed azithromycin accumulation, also prevented the inhibition of HRP uptake. Erythromycylamine, another dicationic macrolide, also inhibited HRP pinocytosis in direct correlation with its cellular accumulation and was as potent as azithromycin at equimolar cellular concns. It is suggested that dicationic macrolides inhibit fluid-phase pinocytosis by impairing the formation of pinocytotic vacuoles and endosomes.
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      Tyteca, D.; Van Der Smissen, P.; Mettlen, M.; Van Bambeke, F.; Tulkens, P. M.; Mingeot-Leclercq, M.; Courtoy, P. J. Azithromycin, a lysosomotropic antibiotic, has distinct effects on fluid-phase and receptor-mediated endocytosis, but does not impair phagocytosis in J774 macrophages. Exp. Cell Res. 2002, 281, 86– 100,  DOI: 10.1006/excr.2002.5613
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      Azithromycin, a Lysosomotropic Antibiotic, Has Distinct Effects on Fluid-Phase and Receptor-Mediated Endocytosis, but Does Not Impair Phagocytosis in J774 Macrophages
      Tyteca, Donatienne; Van Der Smissen, Patrick; Mettlen, Marcel; Van Bambeke, Francoise; Tulkens, Paul M.; Mingeot-Leclercq, Marie-Paule; Courtoy, Pierre J.
      Experimental Cell Research (2002), 281 (1), 86-100CODEN: ECREAL; ISSN:0014-4827. (Elsevier Science)
      Pretreatment of J774 mouse macrophages by the dicationic macrolide antibiotic, azithromycin (AZ), selectively inhibited fluid-phase endocytosis of horseradish peroxidase and lucifer yellow, but not phagocytosis of latex beads. AZ delayed sequestration of receptor-bound transferrin and peroxidase-anti-peroxidase immune complexes into cell-surface endocytic pits and vesicles, but did not slow down the subsequent rate of receptor-mediated endocytosis. AZ down-regulated cell surface transferrin receptors, but not Fcγ receptors, by causing a major delay in the accessibility of internalized transferrin receptors to the recycling route, without slowing down subsequent efflux, resulting in redistribution of the surface pool to an intracellular pool. Acidotropic accumulation of AZ was assocd. with an extensive vacuolation of late endosomes/lysosomes, and these compartments became unaccessible to horseradish peroxidase and immune complexes, but not to latex beads. The inhibitory profile of AZ cannot be solely accounted for by vacuolation and interference with acidification. AZ may help in dissecting various steps of the endocytic app. such as lateral mobility of receptors at the plasma membrane, formation of clathrin-independent endocytic vesicles, orientation of transferrin receptors into the recycling route, and fusogenicity with lysosomes.
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      Gastaminza, P.; Whitten-Bauer, C.; Chisari, F. V. Unbiased probing of the entire hepatitis C virus life cycle identifies clinical compounds that target multiple aspects of the infection. Proc. Natl. Acad. Sci. 2010, 107, 291– 296,  DOI: 10.1073/pnas.0912966107
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      Unbiased probing of the entire hepatitis C virus life cycle identifies clinical compounds that target multiple aspects of the infection
      Gastaminza, Pablo; Whitten-Bauer, Christina; Chisari, Francis V.
      Proceedings of the National Academy of Sciences of the United States of America (2010), 107 (1), 291-296, S291/1-S291/32CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
      Over 170 million people are chronically infected by the hepatitis C virus (HCV) and at risk for dying from liver cirrhosis and hepatocellular carcinoma. Current therapy is expensive, assocd. with significant side effects, and often ineffective. Discovery of antiviral compds. against HCV traditionally involves a priori target identification followed by biochem. screening and confirmation in cell-based replicon assays. Typically, this results in the discovery of compds. that address a few predetd. targets and are prone to select for escape variants. To attempt to identify antiviral compds. with broad target specificity, we developed an unbiased cell-based screening system involving multiple rounds of infection in a 96-well fonnat. Anal. of a publicly available library of 446 clin. approved drugs identified 33 compds. that targeted both known and previously unexplored aspects of HCV infection, including entry, replication, and assembly. Discovery of novel viral and cellular targets in this manner will broaden the therapeutic armamentarium against this virus, allowing for the development of drug mixts. that should reduce the likelihood of mutational escape.
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      Mingorance, L.; Friesland, M.; Coto-Llerena, M.; Pérez-del-Pulgar, S.; Boix, L.; López-Oliva, J. M.; Bruix, J.; Forns, X.; Gastaminza, P. Selective inhibition of hepatitis C virus infection by hydroxyzine and benztropine. Antimicrob. Agents Chemother. 2014, 58, 3451– 3460,  DOI: 10.1128/AAC.02619-14
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      Selective inhibition of hepatitis C virus infection by hydroxyzine and benztropine
      Mingorance, Lidia; Friesland, Martina; Coto-Llerena, Mairene; Perez-del-Pulgar, Sofia; Boix, Loreto; Lopez-Oliva, Juan Manuel; Bruix, Jordi; Forns, Xavier; Gastaminza, Pablo
      Antimicrobial Agents and Chemotherapy (2014), 58 (6), 3451-3460, 11 pp.CODEN: AMACCQ; ISSN:1098-6596. (American Society for Microbiology)
      Hepatitis C virus (HCV) infection is a major biomedical problem worldwide as it causes severe liver disease in millions of humans around the world. Despite the recent approval of specific drugs targeting HCV replication to be used in combination with alpha interferon (IFN-α) and ribavirin, there is still an urgent need for pangenotypic, interferon-free therapies to fight this genetically diverse group of viruses. In this study, we used an unbiased screening cell culture assay to interrogate a chem. library of compds. approved for clin. use in humans. This system enables identifying nontoxic antiviral compds. targeting every aspect of the viral life cycle, be the target viral or cellular. The aim of this study was to identify drugs approved for other therapeutic applications in humans that could be effective components of combination therapies against HCV. As a result of this anal., we identified 12 compds. with antiviral activity in cell culture, some of which had previously been identified as HCV inhibitors with antiviral activity in cell culture and had been shown to be effective in patients. We selected two novel HCV antivirals, hydroxyzine and benztropine, to characterize them by detg. their specificity and genotype spectrum as well as by defining the step of the replication cycle targeted by these compds. We found that both compds. effectively inhibited viral entry at a postbinding step of genotypes 1, 2, 3, and 4 without affecting entry of other viruses.
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      Arikata, M.; Itoh, Y.; Shichinohe, S.; Nakayama, M.; Ishigaki, H.; Kinoshita, T.; Le, M. Q.; Kawaoka, Y.; Ogasawara, K.; Shimizu, T. Efficacy of clarithromycin against H5N1 and H7N9 avian influenza a virus infection in cynomolgus monkeys. Antiviral Res. 2019, 171, 104591  DOI: 10.1016/j.antiviral.2019.104591
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      Efficacy of clarithromycin against H5N1 and H7N9 avian influenza a virus infection in cynomolgus monkeys
      Arikata, Masahiko; Itoh, Yasushi; Shichinohe, Shintaro; Nakayama, Misako; Ishigaki, Hirohito; Kinoshita, Takaaki; Le, Mai Quynh; Kawaoka, Yoshihiro; Ogasawara, Kazumasa; Shimizu, Takeshi
      Antiviral Research (2019), 171 (), 104591CODEN: ARSRDR; ISSN:0166-3542. (Elsevier B.V.)
      Clarithromycin (CAM), a 14-membered ring macrolide, has anti-inflammatory and immunomodulatory actions and antiviral effects in seasonal influenza virus infection. We examd. the prophylactic and therapeutic efficacy of CAM against H5N1 highly pathogenic and H7N9 low pathogenic avian influenza virus infections in cynomolgus monkeys. CAM suppressed H5N1 virus-induced severe signs of disease in the treated monkeys and inhibited virus propagation in tracheal samples and the prodn. of inflammatory cytokines in the lungs of monkeys infected with H5N1 and H7N9 viruses. The prophylactic administration of CAM showed more suppressive effects on clin. signs of disease and viral titers than did therapeutic administration. Thus, since administration of CAM alone showed a tendency to ameliorate clin. sings and to reduce levels of inflammatory cytokines, the macrolides are expected to have effects in combination with the other antiviral drugs on the prophylactic and treatment of patients with severe avian influenza virus infection, which should be further investigated.
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      A review. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly become a global health pandemic. The lack of effective treatments, coupled with its etiol., has resulted in more than 400,000 deaths at the time of writing. The SARS-CoV-2 genome is highly homologous to that of SARS-CoV, the causative agent behind the 2003 SARS outbreak. Based on prior reports, clinicians have pursued the off-label use of several antiviral drugs, while the scientific community has responded by seeking agents against traditional targets, esp. viral proteases. However, several avenues remain unexplored, including disrupting E and M protein oligomerization, outcompeting host glycan-virus interactions, interfering with the heparan sulfate proteoglycans-virus interaction, and others. In this review, the authors highlight some of these opportunities while summarizing the drugs currently in use against coronavirus 2019 (COVID-19).
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      A review. The epidemic of pneumonia (COVID-19) caused by novel coronavirus (SARS-CoV-2) infection has been listed as a public health emergency of international concern by the World Health Organization (WHO), and its harm degree is defined as a global "pandemic". At present, the efforts of various countries focus on the rapid diagnosis and isolation of patients, as well as to find a treatment that can combat the most serious impact of the disease. The no. of reported COVID-19 virus infections is still increasing. Unfortunately, no drugs or vaccines have been approved for the treatment of human coronaviruses, but there is an urgent need for in-depth research on emerging human infectious coronaviruses. Clarification transmission routes and pathogenic mechanisms, and identification of potential drug treatment targets will promote the development of effective prevention and treatment measures. In the absence of confirmed effective treatments, due to public health emergencies, it is essential to study the possible effects of existing approved antivirals drugs or Chinese herbal medicines for SARS-CoV-2. This review summarizes the epidemiol. characteristics, pathogenesis, virus structure and targeting strategies of COVID-19. Meanwhile, this review also focus on the re-purposing of clin. approved drugs and Chinese herbal medicines that may be used to treat COVID-19 and provide new ideas for the discovery of small mol. compds. with potential therapeutic effects on novel COVID-19.
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      The novel coronavirus, SARS-CoV-2, or 2019-nCoV, which originated in Wuhan, Hubei province, China in December 2019, is a grave threat to public health worldwide. A total of 3,672,238 confirmed cases of coronavirus disease 2019 (COVID-19) and 254,045 deaths were reported globally up to May 7, 2020. However, approved antiviral agents for the treatment of patients with COVID-19 remain unavailable. Drug repurposing of approved antivirals against other viruses such as HIV or Ebola virus is one of the most practical strategies to develop effective antiviral agents against SARS-CoV-2. A combination of repurposed drugs can improve the efficacy of treatment, and structure-based drug design can be employed to specifically target SARS-CoV-2. This review discusses therapeutic strategies using promising antiviral agents against SARS-CoV-2. In addition, structural characterization of potentially therapeutic viral or host cellular targets associated with COVID-19 have been discussed to refine structure-based drug design strategies.
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      Journal of Virology (2021), 95 (3), e01987CODEN: JOVIAM; ISSN:1098-5514. (American Society for Microbiology)
      Severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) has caused a pandemic of historic proportions and continues to spread globally, with enormous consequences to human health. Currently there is no vaccine, effective therapeutic, or prophylactic. As with other betacoronaviruses, attachment and entry of SARS-CoV-2 are mediated by the spike glycoprotein (SGP). In addn. to its well-documented interaction with its receptor, human angiotensin-converting enzyme 2 (hACE2), SGP has been found to bind to glycosaminoglycans like heparan sulfate, which is found on the surface of virtually all mammalian cells. Here, we pseudotyped SARS-CoV-2 SGP on a third-generation lentiviral (pLV) vector and tested the impact of various sulfated polysaccharides on transduction efficiency in mammalian cells. The pLV vector pseudotyped SGP efficiently and produced high titers on HEK293T cells. Various sulfated polysaccharides potently neutralized pLV-S pseudotyped virus with clear structure-based differences in antiviral activity and affinity to SGP. Concn.-response curves showed that pLV-S particles were efficiently neutralized by a range of concns. of unfractionated heparin (UFH), enoxaparin, 6-O-desulfated UFH, and 6-O-desulfated enoxaparin with 50% inhibitory concns. (IC50s) of 5.99 μg/L, 1.08 mg/L, 1.77 μg/L, and 5.86 mg/L, resp. In summary, several sulfated polysaccharides show potent anti-SARS-CoV-2 activity and can be developed for prophylactic as well as therapeutic purposes.
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      Antimicrobial Agents and Chemotherapy (2020), 64 (6), e00754/1-e00754/3CODEN: AMACCQ; ISSN:1098-6596. (American Society for Microbiology)
      The currently unfolding coronavirus pandemic threatens health systems and economies worldwide. The spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the assocd. disease coronavirus disease 2019 (COVID-19) has nitially been limited to China. However, the virus has now been detected in more than 100 countries outside China, and major outbreaks are ongoing in the United States, taly, and Spain. At present, our antiviral arsenal offers little protection against SARS CoV-2, although recent progress has been reported (1), and novel antivirals are urgently needed to mitigate the COVID-19 health crisis. The SARS-CoV-2 spike protein (S) is inserted into the viral envelope and mediates viral entry into cells. For this, the S protein depends on the cellular enzyme transmem brane protease serine 2 (TMPRSS2), which cleaves and thereby activates the S protein (2). SARS-CoV (3-5) and other coronaviruses (6, 7) also use TMPRSS2 for S protein activation, and the protease is expressed in SARS-CoV target cells throughout the human respiratory tract (8). Moreover, TMPRSS2 is required for spread of SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV) in rodent models (9, 10) but is dispensable for development and homeostasis in mice (11). Thus, TMPRSS2 consti tutes an attractive drug target. Recent work shows that camostat mesylate (NI-03), a serine protease inhibitor active against TMPRSS2 and employed for treatment of pancreatitis in Japan, inhibits SARS CoV-2 infection of human lung cells (2). The suitability of camostat mesylate for treatment of COVID-19 is currently being evaluated in a clin. trial (12), but it is unclear whether compd. concns. can be attained in the lung that are sufficient to suppress viral spread. In the absence of this information, testing of other serine protease inhibitors for blockade of SARS-CoV-2 entry is an important task. For this, we tested gabexate mesylate (FOY) and nafamostat mesylate (Futhan) (13) along with camostat mesylate for inhibition of SARS-CoV-2 infection of lung cells. All com pounds are approved for human use in Japan, and nafamostat mesylate inhibits TMPRSS2-dependent host cell entry of MERS-CoV (14). A comparison of the antiviral activities of the three compds. revealed that none interfered with cell viability or with host cell entry mediated by the glycoproteins of vesicular stomatitis virus or Machupo virus (Fig. 1A), which served as neg. controls. Gabexate mesylate slightly inhibited SARS-CoV-2 S-driven host cell entry while camostat mesylate robustly sup pressed entry (Fig. 1A). Notably, nafamostat mesylate, which is FDA approved for indications unrelated to coronavirus infection, inhibited SARS-CoV-2 S-mediated entry.
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      The rapid emergence of COVID-19 pandemics has posed humans particularly vulnerable to the novel SARS-CoV-2 virus. Since de novo drug discovery is both expensive and time-consuming, drug repurposing approaches are believed to be of particular help. The SARS-CoV-2 spike (S) protein is known to attach human angiotensin-converting enzyme-2 (hACE2) through its receptor-binding domain (RBD). We screened 1930 FDA-approved ligands for the selection of optimal ones blocking this interaction. Virtual screening predicted top 25 ligands docking to any of the reported binding sites. After exclusion of those ligands which were unsuitable for systemic use, the remaining 69 RBD-ligand complexes were screened based on the masking capacity of the amino acid residues engaged in RBD-hACE2 interaction, excluding 47 RBD-ligand complexes. A short molecular dynamics (MD) simulation analysis identified 11 globally stable complexes with the lowest RMSD (root-mean-square deviation). Next, a moderately long MD analysis revealed those six RBD-ligand complexes with the lowest RMSD variation, as a measure of global stability. Finally, a long MD analysis revealed two select candidate ligands, including ritonavir and naloxegol, highly stabilizing those key residues engaged in RBD-hACE2 interaction. A similar MD analysis of a few antiviral drugs which are under clinical trials or approved for COVID-19 treatment showed them inferior to both select ligands in terms of stabilizing the RBD globally and locally at binding sites. Because of the crucial role of the S protein in virus virulence, our results highly propose ritonavir and naloxegol as the potentially helpful therapeutics against COVID-19, mandating appropriate clinical trials. Communicated by Ramaswamy H. Sarma.
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      COVID-19, which has emerged recently as a pandemic viral infection caused by SARS-coronavirus 2 has spread rapidly around the world, creating a public health emergency. The current situation demands an effective therapeutic strategy to control the disease using drugs that are approved, or by inventing new ones. The present study examines the possible repurposing of existing anti-viral protease inhibitor drugs. For this, the structural features of the viral spike protein, the substrate for host cell protease and main protease of the available SARS CoV-2 isolates were established by comparing with related viruses for which antiviral drugs are effective. The results showed 97% sequence similarity among SARS and SARS-CoV-2 main protease and has same cleavage site positions and ACE2 receptor binding region as in the SARS-CoV spike protein. Though both are N-glycosylated, unlike SARS-CoV, human SARS-CoV-2 S-protein was O-glycosylated as well. Molecular docking studies were done to explore the role of FDA approved protease inhibitors to control SARS-CoV-2 replication. The results indicated that, Ritonavir has the highest potency to block SARS-CoV-2 main protease and human TMPRSS2, a host cell factor that aids viral infection. Other drugs such as Indinavir and Atazanavir also showed favourable binding with Cathepsin B/L that helped viral fusion with the host cell membrane. Further molecular dynamics simulation and MM-PBSA binding free energy calculations confirmed the stability of protein-drug complexes. These results suggest that protease inhibitors particularly Ritonavir, either alone or in combination with other drugs such as Atazanavir, have the potential to treat COVID 19. Communicated by Ramaswamy H. Sarma.
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      OBJECTIVE: Modern machine learning-based modeling methods are increasingly applied to clinical problems. One such application is in variable selection methods for predictive modeling. However, there is limited research comparing the performance of classic and modern for variable selection in clinical datasets. MATERIALS AND METHODS: We analyzed the performance of eight different variable selection methods: four regression-based methods (stepwise backward selection using p-value and AIC, Least Absolute Shrinkage and Selection Operator, and Elastic Net) and four tree-based methods (Variable Selection Using Random Forest, Regularized Random Forests, Boruta, and Gradient Boosted Feature Selection). We used two clinical datasets of different sizes, a multicenter adult clinical deterioration cohort and a single center pediatric acute kidney injury cohort. Method evaluation included measures of parsimony, variable importance, and discrimination. RESULTS: In the large, multicenter dataset, the modern tree-based Variable Selection Using Random Forest and the Gradient Boosted Feature Selection methods achieved the best parsimony. In the smaller, single-center dataset, the classic regression-based stepwise backward selection using p-value and AIC methods achieved the best parsimony. In both datasets, variable selection tended to decrease the accuracy of the random forest models and increase the accuracy of logistic regression models. CONCLUSIONS: The performance of classic regression-based and modern tree-based variable selection methods is associated with the size of the clinical dataset used. Classic regression-based variable selection methods seem to achieve better parsimony in clinical prediction problems in smaller datasets while modern tree-based methods perform better in larger datasets.
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      A review. Computational methods for target prediction, based on mol. similarity and network-based approaches, machine learning, docking and others, have evolved as valuable and powerful tools to aid the challenging task of mode of action identification for bioactive small mols. such as drugs and drug-like compds. Ideally, large-scale prospective expts. are conducted to validate the performance of a model; however, this expensive and time-consuming endeavor is often not feasible. Therefore, to est. the predictive power of a method, statistical validation based on retrospective knowledge is commonly used. There are multiple statistical validation techniques that vary in rigor. In this review we discuss the validation strategies employed, highlighting the usefulness and constraints of the validation schemes and metrics that are employed to measure and describe performance. We address the limitations of measuring only generalized performance, given that the underlying bioactivity and structural data are biased towards certain small-mol. scaffolds and target families, and suggest addnl. aspects of performance to consider in order to produce more detailed and realistic ests. of predictive power. Finally, we describe the validation strategies that were employed by some of the most thoroughly validated and accessible target prediction methods.
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      The study of hepatitis C virus (HCV), a major cause of chronic liver disease, was hampered by the lack of a cell culture system supporting its replication. Here, the authors have successfully generated infectious pseudo-particles that were assembled by displaying unmodified and functional HCV glycoproteins onto retroviral and lentiviral core particles. The presence of a green fluorescent protein marker gene packaged within these HCV pseudo-particles allowed reliable and fast detn. of infectivity mediated by the HCV glycoproteins. Primary hepatocytes as well as hepato-carcinoma cells were found to be the major targets of infection in vitro. High infectivity of the pseudo-particles required both E1 and E2 HCV glycoproteins, and was neutralized by sera from HCV-infected patients and by some anti-E2 monoclonal antibodies. In addn., these pseudo-particles allowed investigation of the role of putative HCV receptors. Although our results tend to confirm their involvement, they provide evidence that neither LDLr nor CD81 is sufficient to mediate HCV cell entry. Altogether, these studies indicate that these pseudo-particles may mimic the early infection steps of parental HCV and will be suitable for the development of much needed new antiviral therapies.
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