Institute of Microbiology, University Hospital of Lausanne, University of Lausanne, 1011 Lausanne, Switzerland.
Department of Organic Chemistry, University of Chemistry and Technology Prague, 16628 Prague 6, Czech Republic.
J Chem Inf Model. 2024 Aug 12;64(15):6190-6196. doi: 10.1021/acs.jcim.4c00758. Epub 2024 Jul 22.
We currently lack antivirals for most human viruses. In a quest for new molecules, focusing on viral RNA, instead of viral proteins, can represent a promising strategy. In this study, new inhibitors were identified starting from a published crystal structure of the tertiary SARS-CoV-2 RNA involved in the -1 programmed ribosomal frameshift. The pseudoknot structure was refined, and a virtual screening was performed using the repository of binders to the nucleic acid library, taking into consideration RNA flexibility. Hit compounds were validated against the wild-type virus and with a dual-luciferase assay measuring the frameshift efficiency. Several active molecules were identified. Our study reveals new inhibitors of SARS-CoV-2 but also highlights the feasibility of targeting RNA starting from virtual screening, a strategy that could be broadly applied to drug development.
我们目前缺乏大多数人类病毒的抗病毒药物。在寻找新分子的过程中，专注于病毒 RNA 而不是病毒蛋白可能是一种有前途的策略。在这项研究中，我们从已发表的涉及 -1 核糖体移码的 SARS-CoV-2 三级 RNA 的晶体结构开始，确定了新的抑制剂。我们对假结结构进行了细化，并使用核酸文库的结合物库进行了虚拟筛选，同时考虑了 RNA 的灵活性。用野生型病毒和测量移码效率的双荧光素酶测定法对命中化合物进行了验证。鉴定出了几种活性分子。我们的研究揭示了 SARS-CoV-2 的新抑制剂，但也强调了从虚拟筛选开始靶向 RNA 的可行性，这一策略可能广泛应用于药物开发。
