The ongoing COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is partly under control by vaccination. However, highly potent and safe antiviral drugs for SARS-CoV-2 are still needed to avoid development of severe COVID-19. We report the discovery of a small molecule, Z-Tyr-Ala-CHN2, which was identified in a cell-based antiviral screen. The molecule exerts sub-micromolar antiviral activity against SARS-CoV-2, SARS-CoV-1, and human coronavirus 229E. Time-of-addition studies reveal that Z-Tyr-Ala-CHN2 acts at the early phase of the infection cycle, which is in line with the observation that the molecule inhibits cathepsin L. This results in antiviral activity against SARS-CoV-2 in VeroE6, A549-hACE2, and HeLa-hACE2 cells, but not in Caco-2 cells or primary human nasal epithelial cells since the latter two cell types also permit entry via transmembrane protease serine subtype 2 (TMPRSS2). Given their cell-specific activity, cathepsin L inhibitors still need to prove their value in the clinic; nevertheless, the activity profile of Z-Tyr-Ala-CHN2 makes it an interesting tool compound for studying the biology of coronavirus entry and replication.

中文翻译：

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Z-Tyr-Ala-CHN2 的鉴定，这是一种组织蛋白酶 L 抑制剂，具有针对冠状病毒（包括 SARS-CoV-2）的广谱细胞特异性活性。


由严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2) 引起的持续的 COVID-19 大流行已通过疫苗接种得到部分控制。然而，仍然需要针对 SARS-CoV-2 的高效且安全的抗病毒药物，以避免发展为严重的 COVID-19。我们报告了一种小分子 Z-Tyr-Ala-CHN2 的发现，它是在基于细胞的抗病毒筛选中鉴定出来的。该分子对 SARS-CoV-2、SARS-CoV-1 和人类冠状病毒 229E 发挥亚微摩尔抗病毒活性。添加时间研究表明，Z-Tyr-Ala-CHN2 在感染周期的早期阶段起作用，这与该分子抑制组织蛋白酶 L 的观察结果一致。这导致针对 SARS-CoV-2 的抗病毒活性在 VeroE6、A549-hACE2 和 HeLa-hACE2 细胞中，但在 Caco-2 细胞或原代人鼻上皮细胞中则不然，因为后两种细胞类型也允许通过跨膜蛋白酶丝氨酸亚型 2 (TMPRSS2) 进入。鉴于其细胞特异性活性，组织蛋白酶 L 抑制剂仍需要证明其在临床中的价值；尽管如此，Z-Tyr-Ala-CHN2 的活性特征使其成为研究冠状病毒进入和复制生物学的有趣工具化合物。