Discovery of a Novel Inhibitor of Coronavirus 3CL Protease for the Potential Treatment of COVID-19.
Britton BorasRhys M JonesBrandon J AnsonDan ArensonLisa AschenbrennerMalina A BakowskiNathan BeutlerJoseph BinderEmily ChenHeather EngHolly HammondJennifer HammondRobert E HauptRobert L HoffmanEugene P KadarRob KaniaEmi KimotoMelanie G KirkpatrickLorraine LanyonEmma K LendyJonathan R LillisJames LogueSuman A LuthraChunlong MaStephen W MasonMarisa E McGrathStephen NoellR Scott ObachMatthew N O'Brien LaramyRebecca O'ConnorKevin OgilvieDafydd R OwenMartin PetterssonMatthew R ReeseThomas F RogersMichelle I RossulekJean G SathishNorimitsu ShiraiClaire SteppanMartyn TicehurstLawrence W UpdykeStuart WestonYuao ZhuJun WangArnab K ChatterjeeAndrew D MesecarMatthew B FriemanAnnaliesa S AndersonCharlotte AllertonPublished in: bioRxiv : the preprint server for biology (2021)
COVID-19 caused by the SARS-CoV-2 virus has become a global pandemic. 3CL protease is a virally encoded protein that is essential across a broad spectrum of coronaviruses with no close human analogs. The designed phosphate prodrug PF-07304814 is metabolized to PF-00835321 which is a potent inhibitor in vitro of the coronavirus family 3CL pro, with selectivity over human host protease targets. Furthermore, PF-00835231 exhibits potent in vitro antiviral activity against SARS-CoV-2 as a single agent and it is additive/synergistic in combination with remdesivir. We present the ADME, safety, in vitro , and in vivo antiviral activity data that supports the clinical evaluation of this compound as a potential COVID-19 treatment.