The influenza A virus M2 proton channel (A/M2) is the target of the antiviral drugs, amantadine and rimantadine, whose use have been discontinued due to widespread drug resistance. Among the handful of drug-resistant mutants of M2, S31N, V27A and L26F were found in more than 99% of the currently circulating viruses. Discovery of inhibitors targeting these M2 mutants has been hampered by the lack of structural information and their limited sizes, polarity, and dynamic nature of their drug binding sites. Nevertheless, using an integrated approach including medicinal chemistry, molecular dynamics simulation, solid/solution-state NMR, X-ray crystallography, and pharmacological characterizations, we have discovered small molecule drugs that inhibit mutant M2 (S31N, V27A and L26F) with potencies greater than amantadine's potency against WT M2. A few compounds exhibiting EC50 around 100 nM are advanced to mice model studies. Structural characterization of S31N drug binding by NMR shows the drug bound in the homotetrameric channel, threaded between the side chains of Asn31.   The S31N inhibitors, like other potent WT M2 inhibitors, contain a charged ammonium group. The ammonium binds as a hydrate to one of three sites aligned along the central cavity that appear to be hotspots for inhibition. These drug binding hotspots along the channel axis provide a general model of M2 inhibition that can be used to guide the design of other channel blockers.

Structure and inhibition of the drug-resistant mutants of the M2 proton channel of influenza A virus

246th National Meeting (2013)

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