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bioRxiv · 10.1101/2021.04.02.438204

Discovery and in-vitro evaluation of potent SARS-CoV-2 entry inhibitors

Acharya, A.·Pandey, K.·Thurman, M.·Klug, E.·Trivedi, J.·Lorson, C. L.·Singh, K.·Byrareddy, S. N.
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Abstract

SARS-CoV-2 infection initiates with the attachment of spike protein to the ACE2 receptor. While vaccines have been developed, no SARS-CoV-2 specific small molecule inhibitors have been approved. Herein, utilizing the crystal structure of the ACE2/Spike receptor binding domain (S-RBD) complex in computer-aided drug design (CADD) approach, we docked [~]8 million compounds within the pockets residing at S-RBD/ACE2 interface. Five best hits depending on the docking score, were selected and tested for their in vitro efficacy to block SARS-CoV-2 replication. Of these, two compounds (MU-UNMC-1 and MU-UNMC-2) blocked SARS-CoV-2 replication at sub-micromolar IC50 in human bronchial epithelial cells (UNCN1T) and Vero cells. Furthermore, MU-UNMC-2 was highly potent in blocking the virus entry by using pseudoviral particles expressing SARS-CoV-2 spike. Finally, we found that MU-UNMC-2 is highly synergistic with remdesivir (RDV), suggesting that minimal amounts are needed when used in combination with RDV, and has the potential to develop as a potential entry inhibitor for COVID-19.

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Acharya, A., Pandey, K., Thurman, M., Klug, E., Trivedi, J., Lorson, C. L., Singh, K., Byrareddy, S. N.. 2021-04-02. Discovery and in-vitro evaluation of potent SARS-CoV-2 entry inhibitors. https://doi.org/10.1101/2021.04.02.438204

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