(1384-A) The search for small molecule, non-nucleoside inhibitors of SARS-CoV-2 RNA-Dependent RNA Polymerase

Abstract: The recent COVID-19 pandemic highlights an unmet need for anti-infective treatments against RNA viruses with pandemic potential. Virally encoded RNA-dependent RNA polymerases (RdRps), an essential component of RNA virus replication and transcription, represent a strong target for antiviral therapeutics. In the case of SARS-CoV-2, the etiological agent of COVID-19, the RdRp functions as a trimeric complex comprised of the nsp12 polymerase core and accessory proteins nsp7 and nsp8. Toward the development of novel non-nucleoside SARS-CoV-2 RdRp antiviral therapeutic agents, we undertook a high-throughput screening campaign. Using biochemical assays, we evaluated a panel of prior art compounds gleaned from the literature and multiple small molecule libraries for inhibition of SARS-CoV-2 RdRp activity. The top hits from these libraries were evaluated against full-length, firefly luciferase reporter SARS-CoV-2 virus inside a BSL-3 laboratory to identify compounds with antiviral activity and limited cytotoxicity.