Identification of Potent Small Molecule Inhibitors of SARS-CoV-2 Entry

Jablonski, S.; Mou, H.; Otsuka, Y.; Jablonski, J.; Adcock, R. S.; Batra, L.; Chung, D.; Rood, C.; de Vera, I. M.; Rahaim, R.; Ullah, S.; Yu, X.; Nguyen, T.-T.; Hull, M. V.; Chen, E.; Bannister, T.; Baillargeon, P.; Scampavia, L.; Farzan, M.; Valente, S.; Spicer, T.

doi:10.1101/2021.08.05.455262

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bioRxiv · 10.1101/2021.08.05.455262

Identification of Potent Small Molecule Inhibitors of SARS-CoV-2 Entry

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Abstract

The severe acute respiratory syndrome coronavirus 2 responsible for COVID-19 remains a persistent threat to mankind, especially for the immunocompromised and elderly for which the vaccine may have limited effectiveness. Entry of SARS-CoV-2 requires a high affinity interaction of the viral spike protein with the cellular receptor angiotensin-converting enzyme 2. Novel mutations on the spike protein correlate with the high transmissibility of new variants of SARS-CoV-2, highlighting the need for small molecule inhibitors of virus entry into target cells. We report the identification of such inhibitors through a robust high-throughput screen testing 15,000 small molecules from unique libraries. Several leads were validated in a suite of mechanistic assays, including whole cell SARS-CoV-2 infectivity assays. The main lead compound, Calpeptin, was further characterized using SARS-CoV-1 and the novel SARS-CoV-2 variant entry assays, SARS-CoV-2 protease assays and molecular docking. This study reveals Calpeptin as a potent and specific inhibitor of SARS-CoV-2 and some variants.

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Jablonski, S., Mou, H., Otsuka, Y., Jablonski, J., Adcock, R. S., Batra, L., Chung, D., Rood, C., de Vera, I. M., Rahaim, R., Ullah, S., Yu, X., Nguyen, T.-T., Hull, M. V., Chen, E., Bannister, T., Baillargeon, P., Scampavia, L., Farzan, M., Valente, S., Spicer, T.. 2021-08-05. Identification of Potent Small Molecule Inhibitors of SARS-CoV-2 Entry. https://doi.org/10.1101/2021.08.05.455262

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