Meyer Cindy, Garzia Aitor, Miller Michael W, Huggins David J, Myers Robert W, Hoffmann Hans-Heinrich, Ashbrook Alison W, Jannath Syeda Y, Liverton Nigel, Kargman Stacia, Zimmerman Matthew, Nelson Andrew M, Sharma Vijeta, Dolgov Enriko, Cangialosi Julianna, Penalva-Lopez Suyapa, Alvarez Nadine, Chang Ching-Wen, Oswal Neelam, Gonzalez Irene, Rasheed Risha, Goldgirsh Kira, Davis Jada A, Ramos-Espiritu Lavoisier, Menezes Miriam-Rose, Larson Chloe, Nitsche Julius, Ganichkin Oleg, Alwaseem Hanan, Molina Henrik, Steinbacher Stefan, Glickman J Fraser, Perlin David S, Rice Charles M, Meinke Peter T, Tuschl Thomas
Laboratory for RNA Molecular Biology, The Rockefeller University, New York, NY, USA.
Sanders Tri-Institutional Therapeutics Discovery Institute, The Rockefeller University, New York, NY, USA.
Nature. 2025 Jan;637(8048):1178-1185. doi: 10.1038/s41586-024-08320-0. Epub 2024 Dec 11.
Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The rapid development of highly effective vaccines against SARS-CoV-2 has altered the trajectory of the pandemic, and antiviral therapeutics have further reduced the number of COVID-19 hospitalizations and deaths. Coronaviruses are enveloped, positive-sense, single-stranded RNA viruses that encode various structural and non-structural proteins, including those critical for viral RNA replication and evasion from innate immunity. Here we report the discovery and development of a first-in-class non-covalent small-molecule inhibitor of the viral guanine-N7 methyltransferase (MTase) NSP14. High-throughput screening identified RU-0415529, which inhibited SARS-CoV-2 NSP14 by forming a unique ternary S-adenosylhomocysteine (SAH)-bound complex. Hit-to-lead optimization of RU-0415529 resulted in TDI-015051 with a dissociation constant (K) of 61 pM and a half-maximal effective concentration (EC) of 11 nM, inhibiting virus infection in a cell-based system. TDI-015051 also inhibited viral replication in primary small airway epithelial cells and in a transgenic mouse model of SARS CoV-2 infection with an efficacy comparable with the FDA-approved reversible covalent protease inhibitor nirmatrelvir. The inhibition of viral cap methylases as an antiviral strategy is also adaptable to other pandemic viruses.
2019年冠状病毒病（COVID-19）由严重急性呼吸综合征冠状病毒2（SARS-CoV-2）引起。针对SARS-CoV-2的高效疫苗的迅速研发改变了疫情的发展轨迹，抗病毒疗法进一步减少了COVID-19的住院人数和死亡人数。冠状病毒是有包膜的、正义单链RNA病毒，可编码多种结构和非结构蛋白，包括对病毒RNA复制和逃避先天免疫至关重要的蛋白。在此，我们报告了首个针对病毒鸟嘌呤-N7甲基转移酶（MTase）NSP14的非共价小分子抑制剂的发现和开发。高通量筛选鉴定出RU-0415529，它通过形成独特的三元S-腺苷同型半胱氨酸（SAH）结合复合物来抑制SARS-CoV-2 NSP14。对RU-0415529进行从苗头化合物到先导化合物的优化，得到了TDI-015051，其解离常数（K）为61 pM，半数最大有效浓度（EC）为11 nM，在基于细胞的系统中抑制病毒感染。TDI-015051还在原代小气道上皮细胞和SARS-CoV-2感染的转基因小鼠模型中抑制病毒复制，其疗效与FDA批准的可逆共价蛋白酶抑制剂奈玛特韦相当。抑制病毒帽甲基化酶作为一种抗病毒策略也适用于其他大流行病毒。
