Discovery of Highly Potent Pinanamine-Based Inhibitors against Amantadine- and Oseltamivir-Resistant Influenza A Viruses

Xin Zhao, Runfeng Li, Yang Zhou, Mengjie Xiao, Chunlong Ma, Zhongjin Yang, Shaogao Zeng, Qiuling Du, Chunguang Yang, Haiming Jiang, Yanmei Hu, Kefeng Wang, Chris Ka Pun Mok, Ping Sun, Jianghong Dong, Wei Cui, Jun Wang, Yaoquan Tu, Zifeng Yang, Wenhui Hu

Research output: Contribution to journalArticle

2 Scopus citations

Abstract

Influenza pandemic is a constant major threat to public health caused by influenza A viruses (IAVs). IAVs are subcategorized by the surface proteins hemagglutinin (HA) and neuraminidase (NA), in which they are both essential targets for drug discovery. While it is of great concern that NA inhibitor oseltamivir resistant strains are frequently identified from human or avian influenza virus, structural and functional characterization of influenza HA has raised hopes for new antiviral therapies. In this study, we explored a structure-activity relationship (SAR) of pinanamine-based antivirals and discovered a potent inhibitor M090 against amantadine-resistant viruses, including the 2009 H1N1 pandemic strains, and oseltamivir-resistant viruses. Mechanism of action studies, particularly hemolysis inhibition, indicated that M090 targets influenza HA and it occupied a highly conserved pocket of the HA 2 domain and inhibited virus-mediated membrane fusion by "locking" the bending state of HA 2 during the conformational rearrangement process. This work provides new binding sites within the HA protein and indicates that this pocket may be a promising target for broad-spectrum anti-influenza A drug design and development.

Original languageEnglish (US)
Pages (from-to)5187-5198
Number of pages12
JournalJournal of Medicinal Chemistry
Volume61
Issue number12
DOIs
StatePublished - Jun 28 2018

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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  • Cite this

    Zhao, X., Li, R., Zhou, Y., Xiao, M., Ma, C., Yang, Z., Zeng, S., Du, Q., Yang, C., Jiang, H., Hu, Y., Wang, K., Mok, C. K. P., Sun, P., Dong, J., Cui, W., Wang, J., Tu, Y., Yang, Z., & Hu, W. (2018). Discovery of Highly Potent Pinanamine-Based Inhibitors against Amantadine- and Oseltamivir-Resistant Influenza A Viruses. Journal of Medicinal Chemistry, 61(12), 5187-5198. https://doi.org/10.1021/acs.jmedchem.8b00042