Cellular Engagement of the SARS-CoV-2 Macrodomain by GS-441524 and Enhanced In Vitro Inhibition by its Diphosphorylated Metabolite

Abstract

Coronavirus macrodomains (Mac1) counter host immunity by removing ADP-ribose. GS-441524, the parent nucleoside of remdesivir, inhibits SARS-CoV-2 Mac1, but its active metabolite and cellular engagement were undefined. GS-441524 selectively inhibits SARS-CoV-2 Mac1 over human MacroD2, engages Mac1 in cells but not MERS-CoV Mac1, with its diphosphate metabolite being most potent.