tetano
Editor, Senior Moderator
Cell Rep Med
. 2025 Aug 4:102277.
doi: 10.1016/j.xcrm.2025.102277. Online ahead of print. MERS-related coronavirus circulating in pangolins exhibits strong fusogenicity in human cells and high sensitivity to fusion inhibitors
Shuai Xia[SUP] 1 [/SUP], Fanke Jiao[SUP] 2 [/SUP], Jing Chen[SUP] 3 [/SUP], Lijue Wang[SUP] 2 [/SUP], Tianyu Lu[SUP] 2 [/SUP], Qian Wang[SUP] 2 [/SUP], Wei Xu[SUP] 2 [/SUP], Xinling Wang[SUP] 2 [/SUP], Fei Sun[SUP] 4 [/SUP], Yun Zhu[SUP] 5 [/SUP], Peng Zhou[SUP] 6 [/SUP], Shibo Jiang[SUP] 7 [/SUP], Lu Lu[SUP] 8 [/SUP]
Affiliations
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.
Keywords: MERS-related coronavirus; MjHKU4r-CoV-1; fusion inhibitor; fusogenicity; six-helix bundle.
. 2025 Aug 4:102277.
doi: 10.1016/j.xcrm.2025.102277. Online ahead of print. MERS-related coronavirus circulating in pangolins exhibits strong fusogenicity in human cells and high sensitivity to fusion inhibitors
Shuai Xia[SUP] 1 [/SUP], Fanke Jiao[SUP] 2 [/SUP], Jing Chen[SUP] 3 [/SUP], Lijue Wang[SUP] 2 [/SUP], Tianyu Lu[SUP] 2 [/SUP], Qian Wang[SUP] 2 [/SUP], Wei Xu[SUP] 2 [/SUP], Xinling Wang[SUP] 2 [/SUP], Fei Sun[SUP] 4 [/SUP], Yun Zhu[SUP] 5 [/SUP], Peng Zhou[SUP] 6 [/SUP], Shibo Jiang[SUP] 7 [/SUP], Lu Lu[SUP] 8 [/SUP]
Affiliations
- PMID: 40774246
- DOI: 10.1016/j.xcrm.2025.102277
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.
Keywords: MERS-related coronavirus; MjHKU4r-CoV-1; fusion inhibitor; fusogenicity; six-helix bundle.