Research Center for Influenza and Respiratory Viruses, National Institute of Infectious Diseases, 4-7-1 Gakuen, Musashimurayama, Tokyo, 208-0011, Japan.
Research Center for Influenza and Respiratory Viruses, National Institute of Infectious Diseases, 4-7-1 Gakuen, Musashimurayama, Tokyo, 208-0011, Japan.
Antiviral Res. 2023 Aug;216:105671. doi: 10.1016/j.antiviral.2023.105671. Epub 2023 Jul 13.
The emergence and spread of antiviral-resistant SARS-CoV-2 is of great concern. In this study, we evaluated the propensity of Omicron variants to escape from RNA-dependent RNA polymerase (RdRP) inhibitors and 3C-like protease (3CLpro) inhibitors. SARS-CoV-2 Delta and Omicron variants were serially passaged in vitro in the presence of RdRP inhibitors (remdesivir and molnupiravir) and 3CLpro inhibitors (nirmatrelvir and lufotrelvir) to detect SARS-CoV-2 escape mutants. After five passages with 3CLpro inhibitors, mutant viruses that escaped from 3CLpro inhibitors emerged; however, in the presence of RdRP inhibitors all variants disappeared within 2-4 passages. Our findings suggest that the frequency of SARS-CoV-2 mutant escape from RdRP inhibitors is lower than that from 3CLpro inhibitors. We also found that Delta variants were more likely to acquire amino acid substitutions associated with resistance to 3CLpro inhibitors under the selective pressure of this drug compared with Omicron variants.
抗病毒耐药的 SARS-CoV-2 的出现和传播令人高度关注。在这项研究中，我们评估了奥密克戎变异株逃避 RNA 依赖性 RNA 聚合酶 (RdRP) 抑制剂和 3C 样蛋白酶 (3CLpro) 抑制剂的倾向。在存在 RdRP 抑制剂（瑞德西韦和莫那比拉韦）和 3CLpro 抑制剂（奈玛特韦和利托那韦）的情况下，对 SARS-CoV-2 德尔塔和奥密克戎变异株进行体外连续传代，以检测 SARS-CoV-2 逃逸突变体。经过 3CLpro 抑制剂的 5 次传代，出现了逃避 3CLpro 抑制剂的突变病毒；然而，在 RdRP 抑制剂存在的情况下，所有变异株在 2-4 次传代后都消失了。我们的研究结果表明，SARS-CoV-2 突变体逃避 RdRP 抑制剂的频率低于逃避 3CLpro 抑制剂的频率。我们还发现，与奥密克戎变异株相比，在这种药物的选择性压力下，德尔塔变异株更容易获得与 3CLpro 抑制剂耐药相关的氨基酸取代。
