# Adamantane-based inhibitors of the influenza A M2 proton channel: structure-based design, biological evaluation, and synthetic approaches

## TL;DR

This paper explores the design and testing of adamantane-based drugs to block the influenza A virus's M2 proton channel, including insights into drug resistance and synthetic methods.

## Contribution

The paper presents new structural and synthetic approaches for adamantane-based inhibitors targeting wild-type and mutant AM2 channels.

## Key findings

- X-ray crystal structures of AM2 S31N with second-generation adamantane derivatives are still unavailable.
- Solution NMR and ssNMR studies provide insights into drug inhibition mechanisms.
- Research has produced a library of adamantane-based compounds useful as antivirals.

## 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 high-resolution X-ray crystal structures have been obtained for AM2 wild-type (WT) constructs in complex with adamantanamines, as well as for mutant AM2 channels that confer resistance to amantadine and adamantanamines across different pH levels. For the structure of AM2 S31N channels in complex with second-generation adamantane derivatives, consisting of an amantadine analog linked to an aryl group via a methylene bridge, X-ray crystal structures are still unavailable. These complexes have been studied in some detail to date, primarily using solution NMR spectroscopy in micelles or ssNMR in lipid bilayers, providing insights into the inhibition mechanisms of these drugs. These findings, when combined with advances in computational methods, can inform the design and synthesis of adamantane-based blockers targeting WT and mutant AM2 channels. The most popular testing assays were presented. 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.

Experimental structures and accurate simulations can guide the design and synthesis of adamantanamines that can block AM2 wild-type and mutant AM2-mediated proton conductance.