Research laboratory of William DeGrado, PhD

Inhibitors of the M2 Proton Channel X-ray analysis, published in JACS

DGL grad student Jessica Thomsaton's work describing the inhibitor bound high-resolution X-ray structures of the influenza M2 protein channel was recent published in the Journal of the American Chemical Society. The structures described here should greatly advance the design of new drugs to target emerging and known strains of influenza, very frequently having mutations in the M2 protein yielding their drug resistance.



This work follows up Thomaston's previous works (in 2015 and in 2017) detailing the water networks throughout M2's transmembrane domain pore, likely critical for the proton conduction step that aids viral infection. Here, several inhibitor bound x-ray structures show displacement of several of those critical water molecules as these drugs bind and block the transmembrane pore at one end of the channel. Analysis of molecular dynamics simulations conducted in collaboration with the Kolocouris lab (National and Kapodistrian University of Athens) largely agree with these experimental structures. The data are consistent with the previously proposed mechanism of action of these drugs: that the drugs act as a plug to the protons and water necessary to fill the transmembrane proton conducting pore.