Miller Michael W, Meyer Cindy, Garzia Aitor, Hoffmann Hans-Heinrich, Khan Tanweer A, Egbertson Melissa, Myers Robert W, Liverton Nigel, Kargman Stacia, Davis Jada A, Ganichkin Oleg, Nitsche Julius, Steinbacher Stefan, Dagan Shlomi, Glickman J Fraser, Rice Charles M, Tuschl Thomas, Meinke Peter T, Huggins David J
Sanders Tri-Institutional Therapeutics Discovery Institute, The Rockefeller University, 1230 York Avenue, New York, New York 10065, United States.
Laboratory for RNA Molecular Biology, The Rockefeller University, 1230 York Avenue, New York, New York 10065, United States.
J Med Chem. 2025 Sep 5. doi: 10.1021/acs.jmedchem.5c01155.
We recently reported the discovery of TDI-015051, a first-in-class small-molecule inhibitor of the SARS-CoV-2 guanine-N7 methyltransferase nonstructural protein 14 (NSP14). NSP14 plays a critical role in viral RNA cap synthesis and its inhibition represents a novel antiviral approach. Utilizing systematic structure-activity relationship studies, potent non-nucleoside-based inhibitors with single-digit nanomolar cellular activity were identified from an HTS hit lacking cellular activity. Thermal shift assay data and available crystal structures led us to develop a model of the novel inhibitory ternary complex (NSP14, SAH, inhibitor), which was validated with a crystal structure of the complex. The advances described here enabled a successful proof-of-concept study that validated SARS-CoV-2 NSP14 as a novel drug target for COVID-19 and represent the first demonstration of pharmacological inhibition of viral methyltransferases as a viable avenue for an antiviral therapeutic.
我们最近报道了TDI-015051的发现，它是一种针对严重急性呼吸综合征冠状病毒2（SARS-CoV-2）鸟嘌呤-N7甲基转移酶非结构蛋白14（NSP14）的首创小分子抑制剂。NSP14在病毒RNA帽合成中起关键作用，对其进行抑制代表了一种新型抗病毒方法。通过系统的构效关系研究，从一种缺乏细胞活性的高通量筛选命中物中鉴定出了具有个位数纳摩尔细胞活性的强效非核苷类抑制剂。热位移分析数据和现有的晶体结构促使我们构建了新型抑制性三元复合物（NSP14、S-腺苷高半胱氨酸、抑制剂）的模型，该模型通过复合物的晶体结构得到了验证。本文所述的进展促成了一项成功的概念验证研究，该研究验证了SARS-CoV-2 NSP14作为新型冠状病毒肺炎（COVID-19）的新型药物靶点，并且代表了对病毒甲基转移酶进行药理学抑制作为抗病毒治疗可行途径的首次证明。
