High throughput screening identifies broad-spectrum Coronavirus entry inhibitors

The Covid-19 pandemic highlighted the pressing need for antiviral therapeutics capable of mitigating infection and spread of emerging coronaviruses (CoVs). A promising therapeutic strategy lies in inhibiting viral entry mediated by the Spike (S) glycoprotein. To identify small molecule inhibitors th...

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Bibliographic Details
Published in:bioRxiv 2023-12
Main Authors: Khan, Suman, Efrat Ozer Partuk, Chiaravalli, Jeanne, Kozer, Noga, Shurrush, Khriesto A, Elbaz-Alon, Yael, Scher, Nadav, Giraud, Emilie, Tran-Rajau, Jaouen, Agou, Fabrice, Barr, Haim Michael, Ori Avinoam
Format: Article
Language:English
Subjects:
Coronaviruses
COVID-19
Glycoproteins
High-throughput screening
Patent applications
Severe acute respiratory syndrome coronavirus 2
Spike glycoprotein
Stomatitis
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Summary:The Covid-19 pandemic highlighted the pressing need for antiviral therapeutics capable of mitigating infection and spread of emerging coronaviruses (CoVs). A promising therapeutic strategy lies in inhibiting viral entry mediated by the Spike (S) glycoprotein. To identify small molecule inhibitors that block entry downstream of receptor binding, we established a high-throughput screening (HTS) platform based on pseudoviruses. We employed a three-step process to screen nearly 200,000 small molecules. First, we identified potential inhibitors by assessing their ability to inhibit pseudoviruses bearing the SARS-CoV-2 S glycoprotein. Subsequent counter-screening against pseudoviruses with the Vesicular Stomatitis Virus spike glycoprotein (VSV-G), yielding sixty-five SARS-CoV-2 S-specific inhibitors. These were further tested against pseudoviruses bearing the MERS-CoV S glycoprotein, which uses a different receptor. Out of these, five compounds including the known broad-spectrum inhibitor Nafamostat, were subjected to further validation and tested them against pseudoviruses bearing the S glycoprotein of the alpha, delta, and omicron variants as well as against bona fide SARS-CoV-2 in vitro. This rigorous approach revealed a novel inhibitor and its derivative as a potential broad-spectrum antiviral. These results validate the HTS platform and set the stage for lead optimization and future pre-clinical, in vivo studies.Competing Interest StatementA patent application based on the findings of this paper has been filed.
DOI:10.1101/2023.12.04.569985