2. Academic Validation
  3. Main protease mutants of SARS-CoV-2 variants remain susceptible to nirmatrelvir

Main protease mutants of SARS-CoV-2 variants remain susceptible to nirmatrelvir

  • Bioorg Med Chem Lett. 2022 Apr 15;62:128629. doi: 10.1016/j.bmcl.2022.128629.
Sven Ullrich 1,  Kasuni B Ekanayake 1,  Gottfried Otting 1,  Christoph Nitsche 2
Affiliations

Affiliations

  • 1 Research School of Chemistry, Australian National University, Canberra, ACT, 2601, Australia.
  • 2 Research School of Chemistry, Australian National University, Canberra, ACT, 2601, Australia. Electronic address: [email protected].
PMID: 35182772 DOI: 10.1016/j.bmcl.2022.128629
Abstract

The COVID-19 pandemic continues to be a public health threat. Multiple mutations in the spike protein of emerging variants of SARS-CoV-2 appear to impact on the effectiveness of available vaccines. Specific Antiviral agents are keenly anticipated but their efficacy may also be compromised in emerging variants. One of the most attractive coronaviral drug targets is the main protease (Mpro). A promising Mpro inhibitor of clinical relevance is the peptidomimetic nirmatrelvir (PF-07321332). We expressed Mpro of six SARS-CoV-2 lineages (C.37 Lambda, B.1.1.318, B.1.2, B.1.351 Beta, B.1.1.529 Omicron, P.2 Zeta), each of which carries a strongly prevalent missense mutation (G15S, T21I, L89F, K90R, P132H, L205V). Enzyme kinetics reveal that these Mpro variants are catalytically competent to a similar degree as the wildtype. We show that nirmatrelvir has similar potency against the variants as the wildtype. Our in vitro data suggest that the efficacy of the specific Mpro inhibitor nirmatrelvir is not compromised in current COVID-19 variants.

Keywords

Inhibitors; Main protease; Nirmatrelvir; SARS-CoV-2; Variants.

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