Open AccessDiscovery of Hydrocarbon-Stapled Short α-Helical Peptides as Promising Middle East Respiratory Syndrome Coronavirus (MERS-CoV) Fusion Inhibitors
Author(s) -
Chao Wang,
Shuai Xia,
Peiyu Zhang,
Tianhong Zhang,
Zhao Wang,
Yangli Tian,
Guangpeng Meng,
Shibo Jiang,
Keliang Liu
Publication year - 2018
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/acs.jmedchem.7b01732
Subject(s) - heptad repeat , middle east respiratory syndrome coronavirus , chemistry , peptide , molecular mimicry , coiled coil , lipid bilayer fusion , viral protein , coronavirus , biophysics , middle east respiratory syndrome , protein structure , microbiology and biotechnology , peptide sequence , biochemistry , virology , covid-19 , membrane , virus , biology , immune system , immunology , medicine , pathology , infectious disease (medical specialty) , gene , disease
The hexameric α-helical coiled-coil formed between the C-terminal and N-terminal heptad repeat (CHR and NHR) regions of class I viral fusion proteins plays an important role in mediating the fusion of the viral and cellular membranes and provides a clear starting point for molecular mimicry that drives viral fusion inhibitor design. Unfortunately, such peptide mimicry of the short α-helical region in the CHR of Middle East respiratory syndrome coronavirus (MERS-CoV) spike protein has been thwarted by the loss of the peptide's native α-helical conformation when taken out of the parent protein structure. Here, we describe that appropriate all-hydrocarbon stapling of the short helical portion-based peptide to reinforce its bioactive secondary structure remarkably improves antiviral potency. The resultant stapled peptide P21S10 could effectively inhibit infection by MERS-CoV pseudovirus and its spike protein-mediated cell-cell fusion; additionally, P21S10 exhibits improved pharmacokinetic properties than HR2P-M2, suggesting strong potential for development as an anti-MERS-CoV therapeutic.