Exploring the size limit of templates for inhibitors of the M2 ion channel of influenza A virus

J Med Chem. 2011 Apr 28;54(8):2646-57. doi: 10.1021/jm101334y. Epub 2011 Apr 5.

Abstract

Amantadine inhibits the M2 proton channel of influenza A virus, yet its clinical use has been limited by the rapid emergence of amantadine-resistant virus strains. We have synthesized and characterized a series of polycyclic compounds designed as ring-contracted or ring-expanded analogues of amantadine. Inhibition of the wild-type (wt) M2 channel and the A/M2-S31N and A/M2-V27A mutant ion channels were measured in Xenopus oocytes using two-electrode voltage clamp (TEV) assays. Several bisnoradamantane and noradamantane derivatives inhibited the wt ion channel. The compounds bind to a primary site delineated by Val27, Ala30, and Ser31, though ring expansion restricts the positioning in the binding site. Only the smallest analogue 8 was found to inhibit the S31N mutant ion channel. The structure-activity relationship obtained by TEV assay was confirmed by plaque reduction assays with A/H3N2 influenza virus carrying wt M2 protein.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amantadine / chemistry
  • Amantadine / pharmacology
  • Animals
  • Antiviral Agents / chemistry
  • Antiviral Agents / pharmacology
  • Cell Line
  • Dogs
  • Influenza A virus / drug effects
  • Influenza A virus / growth & development
  • Magnetic Resonance Spectroscopy
  • Models, Molecular
  • Patch-Clamp Techniques
  • Spectrophotometry, Infrared
  • Structure-Activity Relationship
  • Viral Matrix Proteins / antagonists & inhibitors*
  • Viral Matrix Proteins / chemistry
  • Viral Plaque Assay
  • Xenopus

Substances

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