Inhibitors of the M2 Proton Channel Engage and Disrupt Transmembrane Networks of Hydrogen-Bonded Waters.

Water-mediated interactions play key roles in drug binding. In protein sites with sparse polar functionality, a small-molecule approach is often viewed as insufficient to achieve high affinity and specificity. Here we show that small molecules can enable potent inhibition by targeting key waters. The M2 proton channel of influenza A is the target of the antiviral drugs amantadine and rimantadine. Structural studies of drug binding to the channel using X-ray crystallography have been limited because of the challenging nature of the target, with the one previously solved crystal structure limited to 3.5 A resolution. Here we describe crystal structures of amantadine bound to M2 in the Inwardclosed conformation (2.00 A), rimantadine bound to M2 in both the Inwardclosed (2.00 A) and Inwardopen (2.25 A) conformations, and a spiro-adamantyl amine inhibitor bound to M2 in the Inwardclosed conformation (2.63 A). These X-ray crystal structures of the M2 proton channel with bound inhibitors reveal that ammonium gro...