Laboratory for Drug Discovery and Disease Research, Shionogi & Co., Ltd., 1-1, Futaba-cho 3-chome, Toyonaka, Osaka, 561-0825, Japan.
Laboratory for Bio-Drug Discovery, Shionogi & Co., Ltd., 1-1, Futaba-cho 3-chome, Toyonaka, Osaka, 561-0825, Japan.
Biochem Biophys Res Commun. 2023 Feb 19;645:132-136. doi: 10.1016/j.bbrc.2023.01.040. Epub 2023 Jan 14.
The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been a public health concern worldwide. Ensitrelvir (S-217622) has been evaluated as an antiviral treatment for COVID-19, targeting SARS-CoV-2 3C-like protease (3CL). Ensitrelvir has been reported to have comparable antiviral activity against some of the SARS-CoV-2 variants: alpha, beta, gamma, delta, and omicron (BA.1.18). In this paper, we describe that ensitrelvir is effective against newly emerging SARS-CoV-2 variants and globally prevalent 3CL mutations. Ensitrelvir exhibited comparable antiviral activity against SARS-CoV-2 variants, including recently emerging ones: omicron (BA1.1, BA.2, BA.2.75, BA.4, BA.5, BQ.1.1, XBB.1, and XE), mu, lambda, and theta. Genetic surveillance of SARS-CoV-2 3CL, the target of ensitrelvir, was conducted using a public database and identified 11 major 3CL mutations circulating globally (G15S, T21I, T24I, K88R, L89F, K90R, P108S, P132H, A193V, H246Y, and A255V). The 3CL mutation from proline to histidine at amino acid position 132 was especially identified in the omicron variant, with prevalence of 99.69%. Enzyme kinetic assay revealed that these 3CL mutants have enzymatic activity comparable to that of the wild type (WT). Next, we assessed the inhibitory effect of ensitrelvir against mutated 3CL, with it showing inhibitory effects similar to that against the WT. These in vitro data suggest that ensitrelvir will be effective against currently circulating SARS-CoV-2 variants, including omicron variants and those carrying 3CL mutations, which emerging novel SARS-CoV-2 variants could carry.
由严重急性呼吸系统综合征冠状病毒 2（SARS-CoV-2）引起的 2019 年冠状病毒病（COVID-19）大流行一直是全球关注的公共卫生问题。恩赛特韦（S-217622）已被评估为一种用于 COVID-19 的抗病毒治疗药物，针对的是 SARS-CoV-2 的 3C 样蛋白酶（3CL）。据报道，恩赛特韦对一些 SARS-CoV-2 变体具有相当的抗病毒活性：阿尔法、贝塔、伽马、德尔塔和奥密克戎（BA.1.18）。在本文中，我们描述了恩赛特韦对新出现的 SARS-CoV-2 变体和全球流行的 3CL 突变具有疗效。恩赛特韦对 SARS-CoV-2 变体表现出相当的抗病毒活性，包括最近出现的变体：奥密克戎（BA1.1、BA.2、BA.2.75、BA.4、BA.5、BQ.1.1、XBB.1 和 XE）、缪、拉姆达和西塔。使用公共数据库对恩赛特韦的靶标 SARS-CoV-2 的 3CL 进行了遗传监测，发现了全球流行的 11 种主要 3CL 突变（G15S、T21I、T24I、K88R、L89F、K90R、P108S、P132H、A193V、H246Y 和 A255V）。第 132 位氨基酸位置脯氨酸到组氨酸的 3CL 突变尤其在奥密克戎变体中被发现，其流行率为 99.69%。酶动力学分析表明，这些 3CL 突变体具有与野生型（WT）相当的酶活性。接下来，我们评估了恩赛特韦对突变 3CL 的抑制作用，发现其对 WT 的抑制作用相似。这些体外数据表明，恩赛特韦将对目前流行的 SARS-CoV-2 变体有效，包括奥密克戎变体和携带 3CL 突变的变体，而新兴的新型 SARS-CoV-2 变体可能携带这些突变。
