Potent Inhibition of Human Betacoronaviruses by a Short Double-Stapled Peptide Mimicking the HR2 Core Region in Viral Spike Protein
A small hexameric coiled-coil fusion complex formed by the interaction between α-helical motif of heptad repeat 2 (HR2<sub>core</sub>) and HR1 core site (HR1<sub>core</sub>) in human betacoronavirus spike protein plays a crucial role in facilitating membrane fusion. Formation of the six-helix bundle involves the evolutionary conservation of key residues in the HR1<sub>core</sub> region. Therefore, to recapitulate the native conformation of the HR2<sub>core</sub> peptide α-helix and the HR1<sub>core</sub> site conserved residues, we employed hydrocarbon double-stapling. The resulting all-hydrocarbon stapled peptide M2PA shows highly potent and broad-spectrum antiviral activity against SARS-CoV-2 and its emerging variants, as well as other betacoronaviruses tested. Also, M2PA is effective against authentic SARS-CoV-2 infection in vivo, and it possesses outstanding pharmacokinetic properties. This represents the first successful minimization of a pan-coronavirus inhibitor to an HR2<sub>core</sub>-based α-helical peptide, and as such, M2PA peptide stands as a promising candidate for drug development to combat coronavirus pandemics.
Authors
- Junhai Xiao
- Ming Yuan (ORCID: https://orcid.org/0009-0004-8272-181X)
- Xiaomei Zhuang (ORCID: https://orcid.org/0000-0002-0732-3692)
- Yuanzhou Wang
- Yu Yuan (ORCID: https://orcid.org/0009-0004-3534-605X)
- Shibo Jiang (ORCID: https://orcid.org/0000-0001-8283-7135)
- Xusheng Du
- Qian Wang (ORCID: https://orcid.org/0000-0002-0326-4410)
- Weiguo Shi (ORCID: https://orcid.org/0000-0003-3037-1016)
- Huan Wang (ORCID: https://orcid.org/0000-0002-7472-0057)
- Lu Lu (ORCID: https://orcid.org/0000-0002-2255-0391)
- Qing Li (ORCID: https://orcid.org/0000-0002-3579-5494)
- Chao Wang (ORCID: https://orcid.org/0000-0002-7673-0638)
- Fei Wang (ORCID: https://orcid.org/0000-0002-2513-502X)
- Wenpeng Zhang (ORCID: https://orcid.org/0000-0002-7018-930X)
- Jie Zhou (ORCID: https://orcid.org/0000-0003-3533-2198)
- Gang‐Ping Xue (ORCID: https://orcid.org/0000-0002-1135-1768)
- Jiahuang Tu
- Shu Shan Du
- Longbo Zheng
- Binbin Xu (ORCID: https://orcid.org/0009-0006-9881-7407)
Institutions
- Shenyang Pharmaceutical University (CN)
- Shanghai Medical College of Fudan University (CN)
- Czech Academy of Sciences, Institute of Biotechnology (CZ)
- Drug Discovery Laboratory (Norway) (NO)
- Ministry of Education (BD)
- Institute of Pharmacology (CZ)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-08-22
- DOI
- https://doi.org/10.1021/acs.jmedchem.5c01614
- Citations
- 2
- Primary Topic
- SARS-CoV-2 and COVID-19 Research
- Type
- article
- Field-Weighted Citation Impact
- 2.79
Funders
- National Natural Science Foundation of China
- Science and Technology Commission of Shanghai Municipality