Structure-based discovery of Middle East respiratory syndrome coronavirus fusion inhibitor

Lu Lu, Qi Liu, Yun Zhu, Kwok-Hung Chan, Lili Qin, Yuan Li, Qian Wang, Jasper Fuk-Woo Chan, Lanying Du, Fei Yu, Cuiqing Ma, Sheng Ye, Kwok-Yung Yuen (), Rongguang Zhang () and Shibo Jiang ()
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Lu Lu: Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Shanghai Medical College and Institute of Medical Microbiology, Fudan University
Qi Liu: Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Shanghai Medical College and Institute of Medical Microbiology, Fudan University
Yun Zhu: National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences
Kwok-Hung Chan: State Key Laboratory of Emerging Infectious Diseases, Carol Yu Centre for Infection, The University of Hong Kong
Lili Qin: National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences
Yuan Li: Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Shanghai Medical College and Institute of Medical Microbiology, Fudan University
Qian Wang: Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Shanghai Medical College and Institute of Medical Microbiology, Fudan University
Jasper Fuk-Woo Chan: State Key Laboratory of Emerging Infectious Diseases, Carol Yu Centre for Infection, The University of Hong Kong
Lanying Du: Lindsley F. Kimball Research Institute, New York Blood Center
Fei Yu: Lindsley F. Kimball Research Institute, New York Blood Center
Cuiqing Ma: Lindsley F. Kimball Research Institute, New York Blood Center
Sheng Ye: National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences
Kwok-Yung Yuen: State Key Laboratory of Emerging Infectious Diseases, Carol Yu Centre for Infection, The University of Hong Kong
Rongguang Zhang: National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences
Shibo Jiang: Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Shanghai Medical College and Institute of Medical Microbiology, Fudan University

Nature Communications, 2014, vol. 5, issue 1, 1-12

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms4067

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