Transmissible SARS-CoV-2 variants with resistance to clinical protease inhibitors.
Transmissible SARS-CoV-2 variants with resistance to clinical protease inhibitors.
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DOI：
10.1126/sciadv.ade8778
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发表时间：
2023-03-29
影响因子：
56.3
通讯作者：
Devi, Sharmila
中科院分区：
文献类型：
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作者：
Devi, Sharmila
疫苗和药物有助于减轻疾病严重程度，遏制严重急性呼吸综合征冠状病毒2(SARS-CoV-2)的传播。然而，持续的病毒传播、持续进化和不断增加的选择压力有可能产生能够抵抗这些干预的病毒变体。在这里，我们研究了SARS-CoV-2主要蛋白水解酶[MPRO；3C样蛋白水解酶(3CLpro)]的自然变异对蛋白水解酶抑制剂的敏感性。MPRO中多个单一氨基酸的变化导致了对尼马瑞韦(帕昔洛韦的活性成分)的耐药性。另一种临床阶段的抑制剂恩替瑞韦(Xocova)显示出不同的耐药性突变谱。重要的是，系统发育分析表明，这些耐药变异中的几个在将这些药物引入人类群体之前就已经存在，并能够传播。这些结果鼓励对耐药变异的监测，以及开发其他具有不同作用机制和耐药谱的蛋白酶抑制剂和其他抗病毒药物，用于联合治疗。循环中的SARS-CoV-2变异株对病毒蛋白酶药物尼马瑞韦(Paxlovid)和恩替瑞韦(Xocova)具有耐药性。
Vaccines and drugs have helped reduce disease severity and blunt the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, ongoing virus transmission, continuous evolution, and increasing selective pressures have the potential to yield viral variants capable of resisting these interventions. Here, we investigate the susceptibility of natural variants of the main protease [Mpro; 3C-like protease (3CLpro)] of SARS-CoV-2 to protease inhibitors. Multiple single amino acid changes in Mpro confer resistance to nirmatrelvir (the active component of Paxlovid). An additional clinical-stage inhibitor, ensitrelvir (Xocova), shows a different resistance mutation profile. Importantly, phylogenetic analyses indicate that several of these resistant variants have pre-existed the introduction of these drugs into the human population and are capable of spreading. These results encourage the monitoring of resistance variants and the development of additional protease inhibitors and other antiviral drugs with different mechanisms of action and resistance profiles for combinatorial therapy. Circulating SARS-CoV-2 variants show resistance to viral protease drugs, nirmatrelvir (Paxlovid) and ensitrelvir (Xocova).