Identification of potent small molecule inhibitors of SARS-CoV-2 entry
Sonia Mediouni, Huihui Mou, Yuka Otsuka, Joseph Jablonski, Robert S. Adcock, Lalit Batra, Dong-Hoon Chung, Christopher Rood, Ian Mitchelle S. de Vera, Ronald J. Rahaim, Sultan Ullah, Xuerong Yu, Yulia A. Getmanenko, Nicole Kennedy, Chao Wang, Tu-Trinh Nguyen, Mitchell Hull, Emily Chen, Thomas D. Bannister, Pierre Baillargeon, Louis Scampavia, Michael Farzan, Susana T. Valente, Timothy Spicer
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.