Dual‐Locking the SARS‐CoV‐2 Spike Trimer: An Amphipathic Molecular “Bolt” Stabilizes Conserved Druggable Interfaces for Coronavirus Inhibition
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.
Authors
- Liangliang Jiang (ORCID: https://orcid.org/0000-0002-0419-1997)
- Jie Wang (ORCID: https://orcid.org/0000-0001-5541-3679)
- Zhiyi Zhang (ORCID: https://orcid.org/0009-0002-5492-7533)
- Ke Lan (ORCID: https://orcid.org/0000-0003-0423-5520)
- Haoran Peng (ORCID: https://orcid.org/0000-0002-7862-1013)
- Jiayun Wu (ORCID: https://orcid.org/0009-0007-7131-7290)
- Lili Chen (ORCID: https://orcid.org/0000-0002-9965-8990)
- Geng Chen (ORCID: https://orcid.org/0000-0002-3452-9434)
- Tao Yu (ORCID: https://orcid.org/0000-0001-7909-3841)
- Fang Ye (ORCID: https://orcid.org/0000-0002-0312-2412)
- Honglin Li (ORCID: https://orcid.org/0000-0003-2270-1900)
- Lili Zhu (ORCID: https://orcid.org/0000-0003-1957-973X)
- Binghao Zhang (ORCID: https://orcid.org/0009-0006-6779-0889)
- Ke Xu (ORCID: https://orcid.org/0000-0002-3454-8993)
- Xuhong H. Qian (ORCID: https://orcid.org/0000-0001-6777-0673)
- Zhenjiang Zhao (ORCID: https://orcid.org/0000-0002-9706-6158)
- Jingjing He (ORCID: https://orcid.org/0000-0003-0322-4846)
- Shiliang Li (ORCID: https://orcid.org/0000-0003-4414-237X)
- Yucheng Zheng (ORCID: https://orcid.org/0009-0003-1030-5553)
- Yang Du (ORCID: https://orcid.org/0009-0004-8834-8446)
- Ping Zhao
- Huan Ge (ORCID: https://orcid.org/0000-0003-0434-0822)
Institutions
- East China University of Science and Technology (CN)
- Fudan University (CN)
- Wuhan University (CN)
- Shanghai University of Traditional Chinese Medicine (CN)
- Huadong Hospital (CN)
- Chinese University of Hong Kong, Shenzhen (CN)
- East China Normal University (CN)
Publication Details
- Journal
- Advanced Science
- Published
- 2025-04-26
- DOI
- https://doi.org/10.1002/advs.202417534
- Citations
- 4
- Primary Topic
- SARS-CoV-2 and COVID-19 Research
- Type
- article
- Field-Weighted Citation Impact
- 5.58
Funders
- National Natural Science Foundation of China
- Chinese Academy of Sciences
- Shanghai Rising-Star Program
- National Key Research and Development Program of China
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences