Research School of Chemistry, Australian National University, Canberra, ACT, 2601, Australia.
Research School of Chemistry, Australian National University, Canberra, ACT, 2601, Australia.
Bioorg Med Chem Lett. 2022 Apr 15;62:128629. doi: 10.1016/j.bmcl.2022.128629. Epub 2022 Feb 16.
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 (M). A promising M inhibitor of clinical relevance is the peptidomimetic nirmatrelvir (PF-07321332). We expressed M 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 M 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 M inhibitor nirmatrelvir is not compromised in current COVID-19 variants.
新冠疫情仍然是公共卫生的威胁。SARS-CoV-2 新兴变异株的刺突蛋白的多个突变似乎影响了现有疫苗的有效性。人们迫切期待特定的抗病毒药物，但它们在新兴变异株中的疗效也可能受到影响。冠状病毒最有吸引力的药物靶点之一是主蛋白酶（M）。一种有前景的、与临床相关的 M 抑制剂是肽拟态 nirmatrelvir（PF-07321332）。我们表达了六个 SARS-CoV-2 谱系的 M（C.37 Lambda、B.1.1.318、B.1.2、B.1.351 Beta、B.1.1.529 Omicron、P.2 Zeta），它们各自携带一个普遍存在的错义突变（G15S、T21I、L89F、K90R、P132H、L205V）。酶动力学研究表明，这些 M 变异体的催化能力与野生型相似。我们表明，nirmatrelvir 对变异株的活性与野生型相似。我们的体外数据表明，特异性 M 抑制剂 nirmatrelvir 的疗效在当前的新冠病毒变异株中并未受到影响。
