Cell Reports Medicine, 19 August, 2025, DOI：https://doi.org/10.1016/j.xcrm.2025.102277

MERS-related coronavirus circulating in pangolins exhibits strong fusogenicity in human cells and high sensitivity to fusion inhibitors

Shuai Xia, Fanke Jiao, Jing Chen, Lijue Wang, Tianyu Lu, Qian Wang, Wei Xu, Xinling Wang, Fei Sun, Yun Zhu, Peng Zhou, Shibo Jiang, Lu Lu

Abstract

Unlike preceding MERS-related coronaviruses, the recently identified MjHKU4r-CoV-1 strain can directly infect human cells. Nonetheless, its potential pathogenic attributes and underlying molecular mechanisms remain unclear. We find that MjHKU4r-CoV-1 induces significant inflammation, including interleukin (IL)-6 and tumor necrosis factor alpha (TNF-α), and exhibits pronounced fusogenicity mediated by its spike (S) protein, leading to extensive syncytium formation. This suggests the possibility that MjHKU4r-CoV-1 possesses strong pathogenic potential in humans. Further, we successfully reveal the molecular mechanism of MjHKU4r-S-driven membrane fusion by crystallizing the six-helix bundle (6-HB) structure, a fusion apparatus composed of HR1 and HR2 domains. Concurrently, we develop a series of peptide-based fusion inhibitors that target the viral HR1 domain to impede the formation of viral 6-HB. Among these fusion inhibitors, a stapled peptide, MjHKU4r-HR2P10, shows the most potent inhibitory activity against MjHKU4r-CoV-1, MERS-CoV, SARS-CoV-2, and HCoV-OC43 infections at nanomolar level and thus holds considerable promise for further development as effective antiviral agents in clinic.

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