Department of Refractory Viral Infections, National Center for Global Health and Medicine Research Institute, Tokyo, Japan.
Department of Intelligent Network for Infection Control, Tohoku University Hospital, Miyagi, Japan.
Nat Commun. 2021 Jan 28;12(1):668. doi: 10.1038/s41467-021-20900-6.
Except remdesivir, no specific antivirals for SARS-CoV-2 infection are currently available. Here, we characterize two small-molecule-compounds, named GRL-1720 and 5h, containing an indoline and indole moiety, respectively, which target the SARS-CoV-2 main protease (M). We use VeroE6 cell-based assays with RNA-qPCR, cytopathic assays, and immunocytochemistry and show both compounds to block the infectivity of SARS-CoV-2 with EC values of 15 ± 4 and 4.2 ± 0.7 μM for GRL-1720 and 5h, respectively. Remdesivir permitted viral breakthrough at high concentrations; however, compound 5h completely blocks SARS-CoV-2 infection in vitro without viral breakthrough or detectable cytotoxicity. Combination of 5h and remdesivir exhibits synergism against SARS-CoV-2. Additional X-ray structural analysis show that 5h forms a covalent bond with M and makes polar interactions with multiple active site amino acid residues. The present data suggest that 5h might serve as a lead M inhibitor for the development of therapeutics for SARS-CoV-2 infection.
除瑞德西韦外，目前尚无针对 SARS-CoV-2 感染的特效抗病毒药物。在这里，我们描述了两种小分子化合物，分别命名为 GRL-1720 和 5h，它们分别含有吲哚啉和吲哚部分，靶向 SARS-CoV-2 主蛋白酶（M）。我们使用基于 VeroE6 细胞的 RNA-qPCR、细胞病变效应测定和免疫细胞化学测定，结果表明这两种化合物均可抑制 SARS-CoV-2 的感染，GRL-1720 和 5h 的 EC 值分别为 15±4 和 4.2±0.7μM。瑞德西韦在高浓度时允许病毒突破；然而，化合物 5h 可完全阻断 SARS-CoV-2 在体外的感染，而无病毒突破或可检测的细胞毒性。5h 和瑞德西韦联合使用对 SARS-CoV-2 表现出协同作用。额外的 X 射线结构分析表明，5h 与 M 形成共价键，并与多个活性位点氨基酸残基形成极性相互作用。目前的数据表明，5h 可能作为 M 的抑制剂先导物，用于开发针对 SARS-CoV-2 感染的治疗药物。
