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

The Journal of biological chemistry, 2022-06, Vol.298 (6), p.101972-101972, Article 101972 [Peer Reviewed Journal]

2022 The Authors ;Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved. ;2022 The Authors 2022 ;ISSN: 0021-9258 ;EISSN: 1083-351X ;DOI: 10.1016/j.jbc.2022.101972 ;PMID: 35461811

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  • Title:
    Structural basis for the in vitro efficacy of nirmatrelvir against SARS-CoV-2 variants
  • Author: Greasley, Samantha E. ; Noell, Stephen ; Plotnikova, Olga ; Ferre, RoseAnn ; Liu, Wei ; Bolanos, Ben ; Fennell, Kimberly ; Nicki, Jennifer ; Craig, Tim ; Zhu, Yuao ; Stewart, Al E. ; Steppan, Claire M.
  • Subjects: Accelerated Communication ; Beta ; crystal structure ; Lambda ; Mpro ; nirmatrelvir ; Omicron ; PF-07321332 ; SARS-CoV-2 ; VOC
  • Is Part Of: The Journal of biological chemistry, 2022-06, Vol.298 (6), p.101972-101972, Article 101972
  • Description: 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). 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 Mpro 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 Mpro specifically for α, β, γ (K90R), λ (G15S), and ο (P132H). In vitro biochemical enzymatic assay characterization of the enzyme kinetics of the mutant Mpros demonstrates that they are catalytically comparable to wildtype. We found that nirmatrelvir has similar potency against each mutant Mpro 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 Mpro 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.
  • Publisher: United States: Elsevier Inc
  • Language: English
  • Identifier: ISSN: 0021-9258
    EISSN: 1083-351X
    DOI: 10.1016/j.jbc.2022.101972
    PMID: 35461811
  • Source: PubMed Central
    Alma/SFX Local Collection
    DOAJ Directory of Open Access Journals
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