A novel method of resistance for influenza against a channel-blocking antiviral drug.
Effective antivirals are few and far between, and as such, the appearance of resistance toward such treatments is an obvious medical concern. In this article, we analyze the mechanism by which influenza attains resistance toward amantadine, a blocker of the viral M2 H(+) channel. Binding analyses of amantadine to M2 peptides from different viral strains showed that the virus has developed two alternate routes to avoid blockage of its channel: (1) a conventional route, in which the channel no longer binds the blocker and, hence, the blocker cannot exert its inhibitory function; and (2) a novel mechanism, in which binding of the blocker is retained, yet the function of the protein is unaffected. Pore diameter profiles revealed the molecular mechanism by which the virus may attain this novel type of resistance: an increase in the size of the channel. Thus, despite the drug binding the channel, it may not be able to block the pore, since the channel diameter has increased. Our findings may have broad ramifications in the design of new antivirals, and of novel blockers against malfunctioning human channels implicated in disease.
Astrahan
Peleg
P
Department of Biological Chemistry, Alexander Silberman Institute of Life Sciences, Hebrew University, Jerusalem, Israel.
Kass
Itamar
I
Cooper
Matthew A
MA
Arkin
Isaiah T
IT
D000547:Amantadine / Q000378:metabolism / Q000494:pharmacology*; D000595:Amino Acid Sequence; D000998:Antiviral Agents / Q000378:metabolism / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D024882:Drug Resistance, Viral / Q000187:drug effects*; D004578:Electron Spin Resonance Spectroscopy; D006801:Humans; D007473:Ion Channels / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D008954:Models, Biological; D008969:Molecular Sequence Data; D009975:Orthomyxoviridae / Q000145:classification / Q000187:drug effects* / Q000378:metabolism
D000998:Antiviral Agents; D007473:Ion Channels; D000547:Amantadine