New polycyclic dual inhibitors of the wild type and the V27A mutant M2 channel of the influenza A virus with unexpected binding mode

Eur J Med Chem. 2015:96:318-29. doi: 10.1016/j.ejmech.2015.04.030. Epub 2015 Apr 14.

Abstract

Two new polycyclic scaffolds were synthesized and evaluated as anti-influenza A compounds. The 5-azapentacyclo[6.4.0.0(2,10).0(3,7).0(9,11)]dodecane derivatives were only active against the wild-type M2 channel in the low-micromolar range. However, some of the 14-azaheptacyclo[8.6.1.0(2,5).0(3,11).0(4,9).0(6,17).0(12,16)]heptadecane derivatives were dual inhibitors of the wild-type and the V27A mutant M2 channels. The antiviral activity of these molecules was confirmed by cell culture assays. Their binding mode was analysed through molecular dynamics simulations, which showed the existence of distinct binding modes in the wild type M2 channel and its V27A variant.

Keywords: Amantadine; Influenza A; M2 channel; Molecular dynamics; Polycyclic amines; V27A mutant.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antiviral Agents / chemical synthesis
  • Antiviral Agents / chemistry
  • Antiviral Agents / pharmacology*
  • Binding Sites / drug effects
  • Cell Survival / drug effects
  • Cells, Cultured
  • Dogs
  • Dose-Response Relationship, Drug
  • Influenza A virus / drug effects*
  • Influenza A virus / genetics
  • Microbial Sensitivity Tests
  • Models, Molecular
  • Molecular Structure
  • Mutation
  • Polycyclic Compounds / chemical synthesis
  • Polycyclic Compounds / chemistry
  • Polycyclic Compounds / pharmacology*
  • Structure-Activity Relationship
  • Viral Matrix Proteins / antagonists & inhibitors*
  • Viral Matrix Proteins / chemistry
  • Viral Matrix Proteins / genetics

Substances

  • Antiviral Agents
  • M2 protein, Influenza A virus
  • Polycyclic Compounds
  • Viral Matrix Proteins