A Novel Potent and Highly Specific Inhibitor against Influenza Viral N1-N9 Neuraminidases: Insight into Neuraminidase-Inhibitor Interactions

  • J Med Chem. 2016 May 26;59(10):4563-77. doi: 10.1021/acs.jmedchem.5b01863.
Nongluk Sriwilaijaroen  1  2 ,  Sadagopan Magesh ,  Akihiro Imamura ,  Hiromune Ando  3 ,  Hideharu Ishida ,  Miho Sakai ,  Erika Ishitsubo ,  Takanori Hori ,  Setsuko Moriya  4 ,  Takeshi Ishikawa ,  Kazuo Kuwata ,  Takato Odagiri  5 ,  Masato Tashiro  5 ,  Hiroaki Hiramatsu  2 ,  Kenji Tsukamoto  6 ,  Taeko Miyagi  4 ,  Hiroaki Tokiwa ,  Makoto Kiso  3 ,  Yasuo Suzuki  2
Affiliations
  • 1. Department of Preclinical Sciences, Faculty of Medicine, Thammasat University , Pathumthani 12120, Thailand.
  • 2. Health Science Hills, College of Life and Health Sciences, Chubu University , Aichi 487-8501, Japan.
  • 3. Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University , Kyoto 606-8501, Japan.
  • 4. Division of Cancer Glycosylation Research, Institute of Molecular Biomembrane and Glycobiology, Tohoku Pharmaceutical University , Sendai 981-8558, Japan.
  • 5. Influenza Virus Research Center, National Institute of Infectious Diseases , Tokyo 208-0011, Japan.
  • 6. Research Team for Zoonotic Diseases, National Institute of Animal Health , Ibaraki 305-0856, Japan.
PMID: 27095056 DOI: 10.1021/acs.jmedchem.5b01863
Abstract

People throughout the world continue to be at risk for death from influenza A virus, which is always creating a new variant. Here we present a new effective and specific anti-influenza viral neuraminidase (viNA) inhibitor, 9-cyclopropylcarbonylamino-4-guanidino-Neu5Ac2en (cPro-GUN). Like zanamivir, it is highly effective against N1-N9 avian and N1-N2 human viNAs, including H274Y oseltamivir-resistant N1 viNA, due to its C-6 portion still being anchored in the active site, different from the disruption of oseltamivir's C-6 anchoring by H274Y mutation. Unlike zanamivir, no sialidase inhibitory activity has been observed for cPro-GUN against huNeu1-huNeu4 Enzymes. Broad efficacy of cPro-GUN against avian and human influenza viruses in cell cultures comparable to its sialidase inhibitory activities makes cPro-GUN ideal for further development for safe therapeutic or prophylactic use against both seasonal and pandemic influenza.