Structure-based discovery of Middle East respiratory syndrome coronavirus fusion inhibitor
- 28 January 2014
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Communications
- Vol. 5 (1), 3067
- https://doi.org/10.1038/ncomms4067
Abstract
A novel human coronavirus, Middle East respiratory syndrome coronavirus (MERS-CoV), has caused outbreaks of a SARS-like illness with high case fatality rate. The reports of its person-to-person transmission through close contacts have raised a global concern about its pandemic potential. Here we characterize the six-helix bundle fusion core structure of MERS-CoV spike protein S2 subunit by X-ray crystallography and biophysical analysis. We find that two peptides, HR1P and HR2P, spanning residues 998–1039 in HR1 and 1251–1286 in HR2 domains, respectively, can form a stable six-helix bundle fusion core structure, suggesting that MERS-CoV enters into the host cell mainly through membrane fusion mechanism. HR2P can effectively inhibit MERS-CoV replication and its spike protein-mediated cell–cell fusion. Introduction of hydrophilic residues into HR2P results in significant improvement of its stability, solubility and antiviral activity. Therefore, the HR2P analogues have good potential to be further developed into effective viral fusion inhibitors for treating MERS-CoV infection.This publication has 63 references indexed in Scilit:
- Structure of MERS-CoV spike receptor-binding domain complexed with human receptor DPP4Cell Research, 2013
- The Spike Protein of the Emerging Betacoronavirus EMC Uses a Novel Coronavirus Receptor for Entry, Can Be Activated by TMPRSS2, and Is Targeted by Neutralizing AntibodiesJournal of Virology, 2013
- Automated selection of stabilizing mutations in designed and natural proteinsProceedings of the National Academy of Sciences of the United States of America, 2012
- Novel Recombinant Engineered gp41 N-terminal Heptad Repeat Trimers and Their Potential as Anti-HIV-1 Therapeutics or MicrobicidesPublished by Elsevier BV ,2010
- PHENIX: a comprehensive Python-based system for macromolecular structure solutionActa Crystallographica Section D-Structural Biology, 2010
- Addition of a cholesterol group to an HIV-1 peptide fusion inhibitor dramatically increases its antiviral potencyProceedings of the National Academy of Sciences of the United States of America, 2009
- Coot: model-building tools for molecular graphicsActa Crystallographica Section D-Structural Biology, 2004
- Novel Therapies Based on Mechanisms of HIV-1 Cell EntryThe New England Journal of Medicine, 2003
- [20] Processing of X-ray diffraction data collected in oscillation modeMethods in Enzymology, 1997
- 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