High throughput screening identifies broad-spectrum Coronavirus entry inhibitors

Suman Khan; Efrat Ozer Partuk; Jeanne Chiaravalli; Noga Kozer; Khriesto A. Shurrush; Yael Elbaz-Alon; Nadav Scher; Emilie Giraud; Jaouen Tran-Rajau; Fabrice Agou; Haim Michael Barr; Ori Avinoam

doi:10.1016/j.isci.2024.110019

High throughput screening identifies broad-spectrum Coronavirus entry inhibitors

Suman Khan
, Efrat Ozer Partuk
, Jeanne Chiaravalli
, Noga Kozer
, Khriesto A. Shurrush
, Yael Elbaz-Alon
, Nadav Scher
, Emilie Giraud
, Jaouen Tran-Rajau
, Fabrice Agou
, Haim Michael Barr
, Ori Avinoam^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

4 Citations (Scopus)

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Abstract

The Covid-19 pandemic highlighted the need for antivirals against emerging coronaviruses (CoV). Inhibiting Spike (S) glycoprotein-mediated viral entry is a promising strategy. 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 hits that inhibit pseudoviruses bearing the SARS-CoV-2 S glycoprotein. Counter-screening against pseudoviruses with the Vesicular Stomatitis Virus Glycoprotein (VSV-G), yielded 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, which included the known broad-spectrum inhibitor Nafamostat, were subjected to further validation and tested against pseudoviruses bearing the S glycoprotein of the alpha, delta, and omicron variants as well as bona fide SARS-CoV-2. This rigorous approach revealed an unreported inhibitor and its derivative as potential broad-spectrum antivirals.

Original language	English
Article number	110019
Number of pages	21
Journal	iScience
Volume	27
Issue number	6
Early online date	17 May 2024
DOIs	https://doi.org/10.1016/j.isci.2024.110019
Publication status	Published - 21 Jun 2024

Funding

We thank members of the Avinoam laboratory, and The Wohl Drug Discovery Institute of the Nancy and Stephen Grand Israel National Center for Personalized Medicine (G-INCPM) for discussions. We also thank Yosef Shaul, Romano Strobelt and Julia Adler for cell lines and plasmids, and Benjamin Podbilewicz, Clari Valansi and Gideon Schreiber for plasmids, Galit Cohen and Shirly Valter for assisting with compound plating. This research was supported by Israel Science Foundation (grant no. 3729/20), Bina Nurture Program, and the European Research Council (ERC) Proof of Concept Grant (101100758 – Inhibicov). OA also acknowledges funding from the Henry Chanoch Krenter Institute for Biomedical Imaging and Genomics, the Schwartz Reisman Collaborative Science Program, and the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (grant agreement no 851080). OA is an incumbent of the Miriam Berman presidential development chair. This research was also supported in part by funding from the INSTITUT PASTEUR, Research Applications and Industrial Relations Department (DARRI) and the ANRS-MIE (BIOVAR and PRI projects of the EMERGEN research program) to FA.

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title = "High throughput screening identifies broad-spectrum Coronavirus entry inhibitors",

abstract = "The Covid-19 pandemic highlighted the need for antivirals against emerging coronaviruses (CoV). Inhibiting Spike (S) glycoprotein-mediated viral entry is a promising strategy. 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 hits that inhibit pseudoviruses bearing the SARS-CoV-2 S glycoprotein. Counter-screening against pseudoviruses with the Vesicular Stomatitis Virus Glycoprotein (VSV-G), yielded 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, which included the known broad-spectrum inhibitor Nafamostat, were subjected to further validation and tested against pseudoviruses bearing the S glycoprotein of the alpha, delta, and omicron variants as well as bona fide SARS-CoV-2. This rigorous approach revealed an unreported inhibitor and its derivative as potential broad-spectrum antivirals.",

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AU - Elbaz-Alon, Yael

AU - Scher, Nadav

AU - Giraud, Emilie

AU - Tran-Rajau, Jaouen

AU - Agou, Fabrice

AU - Barr, Haim Michael

AU - Avinoam, Ori

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N2 - The Covid-19 pandemic highlighted the need for antivirals against emerging coronaviruses (CoV). Inhibiting Spike (S) glycoprotein-mediated viral entry is a promising strategy. 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 hits that inhibit pseudoviruses bearing the SARS-CoV-2 S glycoprotein. Counter-screening against pseudoviruses with the Vesicular Stomatitis Virus Glycoprotein (VSV-G), yielded 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, which included the known broad-spectrum inhibitor Nafamostat, were subjected to further validation and tested against pseudoviruses bearing the S glycoprotein of the alpha, delta, and omicron variants as well as bona fide SARS-CoV-2. This rigorous approach revealed an unreported inhibitor and its derivative as potential broad-spectrum antivirals.

AB - The Covid-19 pandemic highlighted the need for antivirals against emerging coronaviruses (CoV). Inhibiting Spike (S) glycoprotein-mediated viral entry is a promising strategy. 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 hits that inhibit pseudoviruses bearing the SARS-CoV-2 S glycoprotein. Counter-screening against pseudoviruses with the Vesicular Stomatitis Virus Glycoprotein (VSV-G), yielded 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, which included the known broad-spectrum inhibitor Nafamostat, were subjected to further validation and tested against pseudoviruses bearing the S glycoprotein of the alpha, delta, and omicron variants as well as bona fide SARS-CoV-2. This rigorous approach revealed an unreported inhibitor and its derivative as potential broad-spectrum antivirals.

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High throughput screening identifies broad-spectrum Coronavirus entry inhibitors

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