ArticleAdvanced science (Weinheim, Baden-Wurttemberg, Germany)2025
Dual-Locking the SARS-CoV-2 Spike Trimer: An Amphipathic Molecular "Bolt" Stabilizes Conserved Druggable Interfaces for Coronavirus Inhibition.
Article in Advanced science (Weinheim, Baden-Wurttemberg, Germany), 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.
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Who cites it
3 citing papers in PubMed.
- Article
- A SARS-CoV-2 entry inhibitor trimerizes to lock the spike protein in a closed conformation.bioRxiv : the preprint server for biology · 2025Article
- Dual-Locking the SARS-CoV-2 Spike Trimer: An Amphipathic Molecular "Bolt" Stabilizes Conserved Druggable Interfaces for Coronavirus Inhibition.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
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Authors and funding
22 authors.
Funding
Abstract
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.
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Registered trials
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