Continuously emerging highly pathogenic human coronaviruses (HCoVs) remain a major threat to human health, as illustrated in past SARS-CoV and MERS-CoV outbreaks. The development of a drug with broad-spectrum HCoV inhibitory activity would address this urgent unmet medical need. Although previous studies have suggested that the HR1 of HCoV spike (S) protein is an important target site for inhibition against specific HCoVs, whether this conserved region could serve as a target for the development of broad-spectrum pan-CoV inhibitor remains controversial. Here, we found that peptide OC43-HR2P, derived from the HR2 domain of HCoV-OC43, exhibited broad fusion inhibitory activity against multiple HCoVs.EK1, the optimized form of OC43-HR2P, showed substantially improved pan-CoV fusion inhibitory activity and pharmaceutical properties. Crystal structures indicated that EK1 can form a stable six-helix bundle structure with both short alpha-HCoV and long beta-HCoV HR1s, further supporting the role of HR1 region as a viable pan-CoV target site.
[1]Fudan Univ, Shanghai Publ Hlth Clin Ctr, Shanghai 200032, Peoples R China;
[2]Fudan Univ, Sch Basic Med Sci, Shanghai 200032, Peoples R China;
[3]Fudan Univ, Key Lab Med Mol Virol MOE MOH, Shanghai 200032, Peoples R China;
[4]ShanghaiTech Univ, Shanghai Inst Adv Immunochem Studies, Shanghai 201210, Peoples R China;
[5]Univ Texas Med Branch, Dept Microbiol & Immunol, Galveston, TX 77555 USA;
[6]Jazan Univ, Dept Med Labs Technol, Coll Appl Med Sci, Jazan, Saudi Arabia;
[7]New York Blood Ctr, Lindsley F Kimball Res Inst, New York, NY 10065 USA;
[8]Chinese Ctr Dis Control & Prevent, MOH Key Lab Med Virol, Natl Inst Viral Dis Control & Prevent, Beijing, Peoples R China;
[9]Scripps Res Inst, Dept Integrat Struct & Computat Biol, 10550 North Torrey Pines Rd,BCC206, La Jolla, CA 92037 USA;
[10]Scripps Res Inst, Skaggs Inst Chem Biol, 10550 North Torrey Pines Rd,BCC206, La Jolla, CA 92037 USA
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