Texas A&M Drug Discovery Laboratory, Department of Chemistry, Texas A&M University, College Station, Texas 77843, United States.
Institute of Biosciences and Technology and Department of Translational Medical Sciences, College of Medicine, Texas A&M University, Houston, Texas 77030, United States.
J Med Chem. 2022 Jul 14;65(13):8686-8698. doi: 10.1021/acs.jmedchem.2c00404. Epub 2022 Jun 22.
The U.S. FDA approval of PAXLOVID, a combination therapy of nirmatrelvir and ritonavir has significantly boosted our morale in fighting the COVID-19 pandemic. Nirmatrelvir is an inhibitor of the main protease (M) of SARS-CoV-2. Since many SARS-CoV-2 variants that resist vaccines and antibodies have emerged, a concern of acquired viral resistance to nirmatrelvir naturally arises. Here, possible mutations in M to confer viral evasion of nirmatrelvir are analyzed and discussed from both evolutionary and structural standpoints. The analysis indicates that those mutations will likely reside in the whole aa45-51 helical region and residues including M165, L167, P168, R188, and Q189. Relevant mutations have also been observed in existing SARS-CoV-2 samples. Implications of this analysis to the fight against future drug-resistant viral variants and the development of broad-spectrum antivirals are discussed as well.
美国食品药品监督管理局（FDA）批准了奈玛特韦/利托那韦组合药物（PAXLOVID），这极大地鼓舞了我们抗击 COVID-19 大流行的士气。奈玛特韦是 SARS-CoV-2 主要蛋白酶（M）的抑制剂。由于出现了许多对疫苗和抗体有抵抗力的 SARS-CoV-2 变体，人们自然会担心奈玛特韦获得性病毒耐药性。在这里，从进化和结构的角度分析和讨论了可能导致病毒逃避奈玛特韦的 M 中的突变。分析表明，这些突变可能位于整个 aa45-51 螺旋区域以及包括 M165、L167、P168、R188 和 Q189 在内的残基中。在现有的 SARS-CoV-2 样本中也观察到了相关突变。还讨论了该分析对未来对抗耐药性病毒变体的药物和广谱抗病毒药物开发的影响。
