Structural basis for the in vitro efficacy of nirmatrelvir against SARS-CoV-2 variants.

Autor:	Greasley SE; Medicine Design, Pfizer Worldwide Research, Development & Medical, La Jolla, California, USA., Noell S; Medicine Design, Pfizer Worldwide Research, Development & Medical, Groton, Connecticut, USA., Plotnikova O; Medicine Design, Pfizer Worldwide Research, Development & Medical, Groton, Connecticut, USA., Ferre R; Medicine Design, Pfizer Worldwide Research, Development & Medical, La Jolla, California, USA., Liu W; Medicine Design, Pfizer Worldwide Research, Development & Medical, La Jolla, California, USA., Bolanos B; Medicine Design, Pfizer Worldwide Research, Development & Medical, La Jolla, California, USA., Fennell K; Medicine Design, Pfizer Worldwide Research, Development & Medical, Groton, Connecticut, USA., Nicki J; Medicine Design, Pfizer Worldwide Research, Development & Medical, Groton, Connecticut, USA., Craig T; Medicine Design, Pfizer Worldwide Research, Development & Medical, Groton, Connecticut, USA., Zhu Y; VRD Bacterial Vaccines, Pfizer Worldwide Research, Development & Medical, Pearl River, New York, USA., Stewart AE; Medicine Design, Pfizer Worldwide Research, Development & Medical, La Jolla, California, USA., Steppan CM; Medicine Design, Pfizer Worldwide Research, Development & Medical, Groton, Connecticut, USA. Electronic address: claire.m.steppan@pfizer.com.
Jazyk:	angličtina
Zdroj:	The Journal of biological chemistry [J Biol Chem] 2022 Jun; Vol. 298 (6), pp. 101972. Date of Electronic Publication: 2022 Apr 22.
DOI:	10.1016/j.jbc.2022.101972
Abstrakt:	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 (M pro ) of SARS-CoV-2 and the active protease inhibitor in PAXLOVID (nirmatrelvir tablets and ritonavir tablets). However, the efficacy of nirmatrelvir is underdetermined against evolving SARS-CoV-2 variants. Here, we evaluated the in vitro catalytic activity and potency of nirmatrelvir against the M pro of prevalent variants of concern (VOCs) or variants of interest (VOIs): Alpha (α, B.1.1.7), Beta (β, B.1.351), Delta (δ, B1.617.2), Gamma (γ, P.1), Lambda (λ, B.1.1.1.37/C37), Omicron (ο, B.1.1.529), as well as the original Washington or wildtype strain. These VOCs/VOIs carry prevalent mutations at varying frequencies in the M pro specifically for α, β, γ (K90R), λ (G15S), and ο (P132H). In vitro biochemical enzymatic assay characterization of the enzyme kinetics of the mutant M pros demonstrates that they are catalytically comparable to wildtype. We found that nirmatrelvir has similar potency against each mutant M pro including P132H that is observed in the Omicron variant with a Ki of 0.635 nM as compared to a Ki of 0.933 nM for wildtype. The molecular basis for these observations were provided by solution-phase structural dynamics and structural determination of nirmatrelvir bound to the ο, λ, and β M pro at 1.63 to 2.09 Å 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 VOC/VOI, including Omicron, from replicating in cells. Competing Interests: Conflict of interest All authors are employees of Pfizer, Inc and may hold or own shares of stock. (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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