Design of MERS-CoV entry inhibitory short peptides based on helix-stabilizing strategies

Jichun Li; Qing Li; Shuai Xia; Jiahuang Tu; Longbo Zheng; Qian Wang; Shibo Jiang; Chao Wang

doi:10.1016/j.bmcl.2023.129569

Design of MERS-CoV entry inhibitory short peptides based on helix-stabilizing strategies

Bioorg Med Chem Lett. 2024 Jan 1:97:129569. doi: 10.1016/j.bmcl.2023.129569. Epub 2023 Nov 24.

Authors

Jichun Li¹, Qing Li², Shuai Xia³, Jiahuang Tu², Longbo Zheng⁴, Qian Wang³, Shibo Jiang⁵, Chao Wang⁶

Affiliations

¹ College of Chemical and Pharmaceutical Engineering, Hebei University of Science and Technology, 26 Yuxiang Street, Shijiazhuang 050018, China; State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology & Toxicology, 27 Tai-Ping Road, Beijing 100850, China.
² State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology & Toxicology, 27 Tai-Ping Road, Beijing 100850, China.
³ Key Laboratory of Medical Molecular Virology of MOE/MOH/CAMS, Shanghai Institute of Infectious Disease and Biosecurity, School of Basic Medical Sciences, Fudan University, 131 Dong An Road, Shanghai 200032, China.
⁴ Key Laboratory of Structure-based Drug Design & Discovery of the Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China.
⁵ Key Laboratory of Medical Molecular Virology of MOE/MOH/CAMS, Shanghai Institute of Infectious Disease and Biosecurity, School of Basic Medical Sciences, Fudan University, 131 Dong An Road, Shanghai 200032, China. Electronic address: shibojiang@fudan.edu.cn.
⁶ State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology & Toxicology, 27 Tai-Ping Road, Beijing 100850, China. Electronic address: chaow301@sina.com.

PMID: 38008340
DOI: 10.1016/j.bmcl.2023.129569

Abstract

Interaction between Middle East respiratory syndrome coronavirus (MERS-CoV) spike (S) protein heptad repeat-1 domain (HR1) and heptad repeat-2 domain (HR2) is critical for the MERS-CoV fusion process. This interaction is mediated by the α-helical region from HR2 and the hydrophobic groove in a central HR1 trimeric coiled coil. We sought to develop a short peptidomimetic to act as a MERS-CoV fusion inhibitor by reproducing the key recognition features of HR2 helix. This was achieved by the use of helix-stabilizing strategies, including substitution with unnatural helix-favoring amino acids, introduction of ion pair interactions, and conjugation of palmitic acid. The resulting 23-mer lipopeptide, termed AEEA-C16, inhibits MERS-CoV S protein-mediated cell-cell fusion at a low micromolar level comparable to that of the 36-mer HR2 peptide HR2P-M2. Collectively, our studies provide new insights into developing short peptide-based antiviral agents to treat MERS-CoV infection.

Keywords: Fusion inhibitor; Lipopeptide; MERS-CoV; Membrane fusion; α-Helices.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antiviral Agents* / chemistry
Antiviral Agents* / pharmacology
Lipopeptides / pharmacology
Lipopeptides / therapeutic use
Middle East Respiratory Syndrome Coronavirus* / drug effects
Peptides / chemistry
Protein Conformation, alpha-Helical

Substances

Antiviral Agents
Peptides
Lipopeptides