Adamantyl Amines Activity Study Against Mutant Influenza A M2 Channels Identified a Polycyclic Cage Amine Triple blocker Explored with MD simulations and Solid state NMR

ChemMedChem. 2023 Jun 28:e202300182. doi: 10.1002/cmdc.202300182. Online ahead of print.ABSTRACTWe compared the anti-influenza potencies of 57 adamantyl amines and analogs against influenza A virus with serine-31 M2 proton channel, usually termed as WT M2 channel, which is amantadine sensitive. We also tested a sub-set of these compounds against viruses with the amantadine resistant L26F, V27A, A30T, G34E M2 mutant channels. (a) Four compounds inhibited WT M2 virus in vitro with mid-nanomolar and 27 compounds with sub-micromolar to low micromolar potency. (b) Several compounds inhibited L26F M2 virus in vitro with sub-micromolar to low micromolar potency, but only three compounds blocked by electrophysiology L26F M2-mediated proton current. (c) One compound was a triple blocker by EP of WT, L26F, V27A M2 channels but did not inhibit V27A M2 virus in vitro and one compound inhibited WT, L26F, V27A M2 in vitro without blocking V27A M2 channel. (d) One compound blocked only L26F M2 channel by electrophysiology but did not inhibit virus replication. (e) The triple blocker compound by electrophysiology is as long as rimantadine but could bind and block V27A M2 channel due to the compound's bigger girth as revealed by MD simulations while MAS NMR informed on the interaction of the compound with M2(18-60) WT or L26F or V27A.PMID:37377066 | DOI:10.1002/cmdc.202300182
Source: ChemMedChem - Category: Chemistry Authors: Source Type: research