Abstract
The COVID-19 pandemic continues to be a public health threat with emerging variants of SARS-CoV-2. Nirmatrelvir (PF-07321332) is a reversible, covalent inhibitor targeting the main protease (Mpro) of SARS-CoV-2 and the active protease inhibitor in PAXLOVID™ (nirmatrelvir tablets and ritonavir tablets). One of the predominant SARS-CoV-2 variants emerging is the B.1.1.529 Omicron harboring a mutation at amino acid position 132 in the Mpro changing a proline to a histidine (P132H). In vitro biochemical enzymatic assay characterization of the enzyme kinetics of the Omicron Mpro (P132H) demonstrate that it is catalytically comparable to wildtype and that nirmatrelvir has similar potency against both wildtype and Omicron (P132H) Mpro with Ki of 0.933nM (wildtype) and 0.635nM (P132H) each, respectively. This observation is reinforced by our structural determination of nirmatrelvir bound to the omicron Mpro at 1.63Å resolution. These in vitro data suggest that PAXLOVID has the potential to maintain plasma concentrations of nirmatrelvir many-fold times higher than the amount required to stop the SARS-CoV-2 variant Omicron from replicating in cells.
Competing Interest Statement
All authors are employees of Pfizer, Inc and may hold or own shares of Pfizer stock.
