A pan-coronavirus fusion inhibitor targeting the HR1 domain of human coronavirus spike

Sci Adv. 2019 Apr 10;5(4):eaav4580. doi: 10.1126/sciadv.aav4580. eCollection 2019 Apr.


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 α-HCoV and long β-HCoV HR1s, further supporting the role of HR1 region as a viable pan-CoV target site.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Cell Line
  • Coronavirus / classification
  • Coronavirus / drug effects*
  • Coronavirus / genetics
  • Coronavirus / metabolism*
  • Coronavirus Infections / drug therapy
  • Coronavirus Infections / virology*
  • Disease Models, Animal
  • Humans
  • Membrane Fusion / drug effects
  • Mice
  • Models, Molecular
  • Peptides / chemistry
  • Peptides / pharmacology
  • Phylogeny
  • Protein Conformation
  • Protein Domains
  • Protein Interaction Domains and Motifs / drug effects*
  • Solubility
  • Spike Glycoprotein, Coronavirus / antagonists & inhibitors*
  • Spike Glycoprotein, Coronavirus / chemistry*
  • Viral Fusion Protein Inhibitors / chemistry*
  • Viral Fusion Protein Inhibitors / pharmacology*


  • Peptides
  • Spike Glycoprotein, Coronavirus
  • Viral Fusion Protein Inhibitors