A pan-coronavirus fusion inhibitor targeting the HR1 domain of human coronavirus spike
Top Cited Papers
Open Access
- 5 April 2019
- journal article
- research article
- Published by American Association for the Advancement of Science (AAAS) in Science Advances
- Vol. 5 (4), eaav4580
- https://doi.org/10.1126/sciadv.aav4580
Abstract
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.Keywords
Funding Information
- National Natural Science Foundation of China (81661128041)
- National Natural Science Foundation of China (81672019)
- National Natural Science Foundation of China (81822045)
- National Natural Science Foundation of China (31600619)
- Ministry of Science and Technology of the People’s Republic of China (2016YFC1201000)
- Ministry of Science and Technology of the People’s Republic of China (2016YFC1202901)
- the Shanghai Rising-Star Program (16QA1400300)
- National Megaprojects of China for Major Infectious Diseases (2018ZX10301403)
- the Sanming Project of Medicine in Shenzhen
- Ministry of Science and Technology of the People’s Republic of China (2016YFC1200405)
This publication has 76 references indexed in Scilit:
- Discovery of Seven Novel Mammalian and Avian Coronaviruses in the Genus Deltacoronavirus Supports Bat Coronaviruses as the Gene Source of Alphacoronavirus and Betacoronavirus and Avian Coronaviruses as the Gene Source of Gammacoronavirus and DeltacoronavirusJournal of Virology, 2012
- Cleavage and Activation of the Severe Acute Respiratory Syndrome Coronavirus Spike Protein by Human Airway Trypsin-Like ProteaseJournal of Virology, 2011
- Efficient Activation of the Severe Acute Respiratory Syndrome Coronavirus Spike Protein by the Transmembrane Protease TMPRSS2Journal of Virology, 2010
- PHENIX: a comprehensive Python-based system for macromolecular structure solutionActa crystallographica. Section D, Structural biology, 2010
- MolProbity: all-atom structure validation for macromolecular crystallographyActa crystallographica. Section D, Structural biology, 2009
- Coot: model-building tools for molecular graphicsActa crystallographica. Section D, Structural biology, 2004
- PDB2PQR: an automated pipeline for the setup of Poisson-Boltzmann electrostatics calculationsNucleic Acids Research, 2004
- [20] Processing of X-ray diffraction data collected in oscillation modeMethods in Enzymology, 1997
- NMRPipe: A multidimensional spectral processing system based on UNIX pipesJournal of Biomolecular NMR, 1995
- Peptides corresponding to a predictive alpha-helical domain of human immunodeficiency virus type 1 gp41 are potent inhibitors of virus infection.Proceedings of the National Academy of Sciences of the United States of America, 1994