One of the most pressing problems in biomedical research is the ability of microbes to develop resistance to antibiotics and other drugs. The threat is heightened by the emergence of highly infectious pathogens like the new strain of influenza A that is causing the outbreak of swine flu. The bugs’ nimble tactics are a spur to scientists to find creative methods of penetrating their defenses. But first the defenses have to be exposed.
James Chou and co–first authors Rafal Pielak and Jason Schnell have uncovered the mechanism by which the influenza A virus fends off the long-used adamantane family of antiviral drugs. These drugs zero in on one of the virus’s key components, the M2 proton channel, which softens the virus’s target by balancing acidity or alkalinity across membranes during critical points of infection. The researchers found that the drugs latched onto a pocket between two helices that span the viral membrane, locking the M2 channel closed and dampening infection. Studies by the team showed that the drug-resistant mutant of the virus, S31N, escapes drug binding by introducing a mutation on the helix interface, destabilizing the binding pocket and rendering the drugs ineffective. The open question is whether this insight can lead scientists toward shoring up the helix-to-helix interaction to strengthen the drugs’ effect.
Chou, an HMS associate professor of biological chemistry and molecular pharmacology; Pielak, a graduate student; and Schnell, a former postdoc in Chou’s lab and now a lecturer in biochemistry at the University of Oxford (UK), published their paper online April 21 in Proceedings of the National Academy of Sciences. The findings extend research reported last year in Nature (see Focus, Feb. 22, 2008).
