Adamantane-Based Inhibitors of the Influenza A M2 Proton Channel: Structure-Based Design, Biological Evaluation, and Synthetic Approaches

Abstract

The influenza A matrix 2 (AM2) protein, a prototype of viroporins, conducts protons along a chain of water molecules and ionizable side chains, including histidine-37. Solid-state NMR (ssNMR) and X-ray high-resolution crystal structures have been obtained with AM2 wild-type (WT) constructs in complex with adamantanamines or with mutant AM2 channels that confer resistance to amantadine and adamantanamines at different pH levels. For the structure of AM2 S31N channels in complex with second-generation adamantane derivatives, consisting of an amantadine analog linked with an aryl group through a methylene bridge, X-ray structures are still not available. These complexes have been studied so far in some detail, mainly using solution NMR spectroscopy in micelles or ssNMR in lipid bilayers, providing insights into the inhibition mechanism of these drugs. These findings, when combined with advances in computational methods, can be used for the design, testing, and synthesis of adamantane-based blockers that target WT and mutant AM2 channels. The most popular testing assays were presented. Some selected synthetic chemistry routes leading to complex adamantanamines, other saturated polycyclic amines, and second-generation adamantane-based inhibitors were provided. Extensive and long-term research on the druggable M2 channel has provided the scientific society with fundamental tools of structure-based drug design, a synthetic chemistry toolbox, and a library of adamantane-based compounds that can be useful antivirals due to the frequent viral AM2 mutations.