Exploring the Requirements for the Hydrophobic Scaffold and Polar Amine in Inhibitors of M2 from Influenza A Virus

Inhibitors targeting the influenza A virus M2 (A/M2) proton channel, have lost their effectiveness due to widespread resistance. As a first step in the development of new inhibitors that address this problem, we have screened several focused collections of small molecules using two electrode voltage patch clamp assays (TEVC) on Xenopus laevis Oocyte. Diverse head groups and scaffolds of A/M2 inhibitors have been explored. It has been found that not only amine, but also hydroxyl, aminooxyl, guanidine and amidine compounds are active against the A/M2 proton channel. Moreover, the channel is able to accommodate a wide range of structural variation in the apolar scaffold. This study offers information to guide the next generation of A/M2 proton channel inhibitor design.