4.7 Article

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

期刊

JOURNAL OF MEDICINAL CHEMISTRY
卷 61, 期 12, 页码 5187-5198

出版社

AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.8b00042

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资金

  1. National Natural Science Foundation of China [81302648, 81761128014]
  2. State Scholarship Fund of China Scholarship Council [201604910441, 201600160013]
  3. Youth Innovation Promotion Association CAS [2016319]
  4. Pearl River S&T Nova Program of Guangzhou [201806010115]
  5. Ministry of Science and Technology of China [2015DFM30010]
  6. Science Research Project of the Guangdong Province [2016A050503047]
  7. Science and Technology Development Fund in Macao Special Administrative Region [084/2015/A]
  8. Guangzhou Medical University
  9. State Key Laboratory of Respiratory Disease [SKLRD2016ZJ0002]
  10. Swedish Infrastructure Committee (SNIC)
  11. Health and Medical Research Fund of Hong Kong [17160792]
  12. NIH [AI119187]

向作者/读者索取更多资源

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.

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