文献类型：期刊文献

英文题名：Dual-Locking the SARS-CoV-2 Spike Trimer: An Amphipathic Molecular "Bolt" Stabilizes Conserved Druggable Interfaces for Coronavirus Inhibition

作者：Li, Shiliang[1,2,3];Ye, Fang[4];Zheng, Yucheng[5];Wang, Jie[2];Peng, Haoran[6];Zhu, Lili[2];Chen, Lili[7];Yu, Tao[1];Ge, Huan[2];He, Jiaqi[2];Zhang, Binghao[4];Wu, Jiayun[2];Zhang, Zhiyi[4];Jiang, Liangliang[6];Chen, Geng[4];Zhao, Ping[6];Lan, Ke[5];Zhao, Zhenjiang[2];Qian, Xuhong[1,2];Xu, Ke[5];Du, Yang[4];Li, Honglin[1,2,8]

机构：[1]East China Normal Univ, Innovat Ctr AI & Drug Discovery, Sch Pharm, Shanghai 200062, Peoples R China;[2]East China Univ Sci & Technol, Sch Pharm, Shanghai Key Lab New Drug Design, Shanghai 200237, Peoples R China;[3]Fudan Univ, HuaDong Hosp, Dept Pain Management, Shanghai 200040, Peoples R China;[4]Chinese Univ Hong Kong, Kobilka Inst Innovat Drug Discovery, Sch Med, Shenzhen 518172, Guangdong, Peoples R China;[5]Wuhan Univ, Coll Life Sci, Taikang Ctr Life & Med Sci, State Key Lab Virol & Biosafety, Wuhan 430072, Hubei, Peoples R China;[6]Navy Med Univ, Dept Microbiol, Shanghai 200433, Peoples R China;[7]Shanghai Univ Tradit Chinese Med, Inst Interdisciplinary Integrat Med Res, Shanghai 201203, Peoples R China;[8]Lingang Lab, Shanghai 200031, Peoples R China

年份：2025

卷号：12

期号：27

外文期刊名：ADVANCED SCIENCE

收录：;EI(收录号：20251818334001);WOS:【SCI-EXPANDED(收录号:WOS:001475890500001)】；

基金：The authors sincerely thank Beili Wu from Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Leike Zhang from Wuhan Institute of Virology for their help and useful discussion. This work was supported in part by the National Natural Science Foundation of China (82 150 208 and 82 425 104 to H.L., 82 341 056 and 82 272 307 to K.X., and 32 300 138 to H.P.), the National Key R&D Program of China (2022YFC3400501, 2022YFC3400504, 2023YFC2307800), the grants from the Science, Technology, and Innovation Commission of Shenzhen Municipality (JSGG20210901145200002 and JCYJ20200109150019113), the Kobilka Institute of Innovative Drug Discovery in Shenzhen, and the Science and Technology Foundation of Hubei Province (2022CFA047). S.L. is sponsored by the Shanghai Rising-Star Program (23QA1402800).

语种：英文

外文关键词：amphipathic molecular bolt; druggable interfaces; entry inhibitor; RBD-NTD interface; RBD-RBD interface; SARS-CoV-2; spike trimer stabilization

摘要：The SARS-CoV-2 spike (S) protein, a trimeric structure comprising three receptor binding domains (RBDs) and three N-terminal domains (NTDs), undergoes substantial conformational changes to a fusion-prone open state for angiotensin-converting enzyme 2 (ACE2) binding and host cell infection. Stabilizing its closed state is a key antiviral strategy but remains challenging. Here, we introduce S416, a novel amphipathic molecule acting as a "molecular bolt". Cryo-EM study reveals that S416 binds concurrently to six sites across two distinct druggable interfaces: three molecules at the RBD-RBD interfaces and three at the NTD-RBD interfaces. This unique "dual-locking" mechanism, driven by S416's polar carboxyl head and nonpolar phenylthiazole tail, robustly stabilizes the spike trimer in a locked, closed conformation through strong inter-domain interactions, reducing structural flexibility and atomic fluctuations compared to the apo structure resolved synchronously. Crucially, these RBD-RBD and NTD-RBD interfaces are conserved across human-infecting coronaviruses, suggesting potential as broad-spectrum antiviral targets. Our findings demonstrate that the highly dynamic spike trimer can be effectively stabilized by an amphipathic molecular bolt targeting both the inter- and intra-monomer interfaces, offering a promising strategy against emerging coronaviruses.