Wen Yuanmei, Zhou Jun, Pan Fan, Zheng Peisen, Zhong Fengxia, Yang Sidi, Ma Qianhan, Guo Deyin, Zhang Xumu, Zhou Qifan, Li Yingjun
Shenzhen Key Laboratory of Small Molecule Drug Discovery and Synthesis, Department of Chemistry, Shenzhen Grubbs Institute and Medi-X Pingshan, Southern University of Science and Technology, Shenzhen 518000, China.
Guangzhou National Laboratory, Guangzhou, Guangdong Province 510005, China.
ACS Infect Dis. 2025 Aug 8;11(8):2145-2156. doi: 10.1021/acsinfecdis.4c01044. Epub 2025 Jul 17.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes respiratory infections ranging from mild to severe, posing significant public health risks. The emergence of new variants highlights the need for inhibitors targeting conserved nonstructural proteins like nsp14, a key 7-methyltransferase (MTase) critical for viral RNA capping, immune evasion, and replication. Here, we screened 131 compounds using a drug repurposing approach and identified five candidates that inhibit MTase activity. Bobcat339 showed significant inhibition (IC = 21.6 μM) and binding affinity (Δ = +3.9 °C). It also reduced the replication of HCoV-229E and SARS-CoV-2 in infected Huh7 cells (EC = 29.8 and 28.4 μM, respectively). Molecular docking suggested Bobcat339 binds the SAM-binding pocket of nsp14 MTase. These results identify Bobcat339 as a promising lead for developing selective, non-nucleoside nsp14 inhibitors, supporting further structural optimization and preclinical evaluation.
严重急性呼吸综合征冠状病毒2（SARS-CoV-2）可引发从轻度到重度的呼吸道感染，构成重大公共卫生风险。新变种的出现凸显了针对保守非结构蛋白（如nsp14）的抑制剂的需求，nsp14是一种关键的7-甲基转移酶（MTase），对病毒RNA加帽、免疫逃逸和复制至关重要。在此，我们采用药物重新利用方法筛选了131种化合物，并鉴定出五种抑制MTase活性的候选物。Bobcat339表现出显著抑制作用（IC = 21.6 μM）和结合亲和力（Δ = +3.9 °C）。它还降低了HCoV-229E和SARS-CoV-2在感染的Huh7细胞中的复制（EC分别为29.8和28.4 μM）。分子对接表明Bobcat339结合nsp14 MTase 的SAM结合口袋。这些结果表明Bobcat339是开发选择性、非核苷类nsp14抑制剂的有前景的先导物，支持进一步的结构优化和临床前评估。
