Xia Shuai, Jiao Fanke, Chen Jing, Wang Lijue, Lu Tianyu, Wang Qian, Xu Wei, Wang Xinling, Sun Fei, Zhu Yun, Zhou Peng, Jiang Shibo, Lu Lu
Shanghai Public Health Clinical Center, Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Shanghai Institute of Infectious Disease and Biosecurity, School of Basic Medical Sciences, Shanghai Frontiers Science Center of Pathogenic Microbes and Infection, Fudan University, Shanghai, China.
Shanghai Public Health Clinical Center, Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Shanghai Institute of Infectious Disease and Biosecurity, School of Basic Medical Sciences, Shanghai Frontiers Science Center of Pathogenic Microbes and Infection, Fudan University, Shanghai, China.
Cell Rep Med. 2025 Aug 19;6(8):102277. doi: 10.1016/j.xcrm.2025.102277. Epub 2025 Aug 6.
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.
与之前的中东呼吸综合征相关冠状病毒不同，最近发现的MjHKU4r-CoV-1毒株可直接感染人类细胞。尽管如此，其潜在的致病特性和潜在分子机制仍不清楚。我们发现MjHKU4r-CoV-1会引发显著的炎症反应，包括白细胞介素（IL）-6和肿瘤坏死因子α（TNF-α），并通过其刺突（S）蛋白表现出明显的融合活性，导致广泛的合胞体形成。这表明MjHKU4r-CoV-1在人类中具有强大致病潜力的可能性。此外，我们通过解析由HR1和HR2结构域组成的融合装置六螺旋束（6-HB）结构，成功揭示了MjHKU4r-S驱动膜融合的分子机制。同时，我们开发了一系列靶向病毒HR1结构域的基于肽的融合抑制剂，以阻止病毒6-HB的形成。在这些融合抑制剂中，一种环化肽MjHKU4r-HR2P10在纳摩尔水平对MjHKU4r-CoV-1、中东呼吸综合征冠状病毒、严重急性呼吸综合征冠状病毒2和人冠状病毒OC43感染表现出最有效的抑制活性，因此作为临床上有效的抗病毒药物具有很大的进一步开发前景。
