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. Epub 2016 May 4.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antiviral Agents / chemical synthesis
  • Antiviral Agents / chemistry
  • Antiviral Agents / pharmacology*
  • Chickens
  • Dogs
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Madin Darby Canine Kidney Cells
  • Microbial Sensitivity Tests
  • Models, Molecular
  • Molecular Structure
  • Neuraminidase / antagonists & inhibitors*
  • Neuraminidase / metabolism
  • Orthomyxoviridae / drug effects*
  • Orthomyxoviridae / growth & development
  • Structure-Activity Relationship
  • Virus Replication / drug effects

Substances

  • Antiviral Agents
  • Enzyme Inhibitors
  • Neuraminidase