TY - JOUR
T1 - A Study of the Activity of Adamantyl Amines against Mutant Influenza A M2 Channels Identified a Polycyclic Cage Amine Triple Blocker, Explored by Molecular Dynamics Simulations and Solid-State NMR**
AU - Stampolaki, Μarianna
AU - Hoffmann, Anja
AU - Tekwani, Kumar
AU - Georgiou, Kyriakos
AU - Tzitzoglaki, Christina
AU - Ma, Chunlong
AU - Becker, Stefan
AU - Schmerer, Patrick
AU - Döring, Kristin
AU - Stylianakis, Ioannis
AU - Turcu, Andreea L.
AU - Wang, Jun
AU - Vázquez, Santiago
AU - Andreas, Loren B.
AU - Schmidtke, Michaela
AU - Kolocouris, Antonios
N1 - Publisher Copyright:
© 2023 The Authors. ChemMedChem published by Wiley-VCH GmbH.
PY - 2023/8/15
Y1 - 2023/8/15
N2 - We 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 subset of these compounds against viruses with the amantadine-resistant L26F, V27A, A30T, G34E M2 mutant channels. Four compounds inhibited WT M2 virus in vitro with mid-nanomolar potency, with 27 compounds showing sub-micromolar to low micromolar potency. Several compounds inhibited L26F M2 virus in vitro with sub-micromolar to low micromolar potency, but only three compounds blocked L26F M2-mediated proton current as determined by electrophysiology (EP). One compound was found to be a triple blocker of WT, L26F, V27A M2 channels by EP assays, but did not inhibit V27A M2 virus in vitro, and one compound inhibited WT, L26F, V27A M2 in vitro without blocking V27A M2 channel. One compound blocked only L26F M2 channel by EP, but did not inhibit virus replication. The triple blocker compound is as long as rimantadine, but could bind and block V27A M2 channel due to its larger girth as revealed by molecular dynamics simulations, while MAS NMR informed on the interaction of the compound with M2(18–60) WT or L26F or V27A.
AB - We 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 subset of these compounds against viruses with the amantadine-resistant L26F, V27A, A30T, G34E M2 mutant channels. Four compounds inhibited WT M2 virus in vitro with mid-nanomolar potency, with 27 compounds showing sub-micromolar to low micromolar potency. Several compounds inhibited L26F M2 virus in vitro with sub-micromolar to low micromolar potency, but only three compounds blocked L26F M2-mediated proton current as determined by electrophysiology (EP). One compound was found to be a triple blocker of WT, L26F, V27A M2 channels by EP assays, but did not inhibit V27A M2 virus in vitro, and one compound inhibited WT, L26F, V27A M2 in vitro without blocking V27A M2 channel. One compound blocked only L26F M2 channel by EP, but did not inhibit virus replication. The triple blocker compound is as long as rimantadine, but could bind and block V27A M2 channel due to its larger girth as revealed by molecular dynamics simulations, while MAS NMR informed on the interaction of the compound with M2(18–60) WT or L26F or V27A.
KW - adamantyl amine
KW - electrophysiology
KW - molecular dynamics
KW - mutant influenza A M2 proton channel
KW - solid-state NMR
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U2 - 10.1002/cmdc.202300182
DO - 10.1002/cmdc.202300182
M3 - Article
C2 - 37377066
AN - SCOPUS:85165606571
SN - 1860-7179
VL - 18
JO - ChemMedChem
JF - ChemMedChem
IS - 16
M1 - e202300182
ER -