The team, led by Professor Peijun Zhang, Professor of Structural Biology and Director of the Electron Bioimaging Centre at Diamond Light Source, and Dr Caner Akil, Senior Postdoctoral Researcher and first author of the study, developed a functional viral fusion system and applied in situ cryo-electron tomography to directly observe the full range of viral fusion intermediates. Their findings reveal how the spike protein progresses through extended, partially folded, and fully folded conformations before forming a fusion pore. This sequence is tightly regulated by protease cleavage and receptor binding.
Professor Peijun Zhang said: “Our fusion system provides a comprehensive perspective on spike–ACE2 and spike–antibody interactions, capturing the complete spectrum of fusion intermediates, including many previously unrecognised states, and offers a platform for the development of next-generation fusion inhibitors.”
Dr Caner Akıl added: “This study not only advances our understanding of SARS-CoV-2 fusion mechanisms and the inhibitory action of S2-targeting antibodies, but also holds promise for investigating membrane fusion across a wide range of viral systems.”
Crucially, the study demonstrates how the WS6 S2 antibody binds and clusters prefusion spikes, crosslinking them and preventing the conformational changes required for membrane fusion. These insights deepen our understanding of coronavirus entry and point to promising new strategies for the development of pan-coronavirus antiviral therapies.