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**

Μarianna Stampolaki, Anja Hoffmann, Kumar Tekwani, Kyriakos Georgiou, Christina Tzitzoglaki, Chunlong Ma, Stefan Becker, Patrick Schmerer, Kristin Döring, Ioannis Stylianakis, Andreea L. Turcu, Jun Wang, Santiago Vázquez, Loren B. Andreas, Michaela Schmidtke, Antonios Kolocouris

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article numbere202300182
JournalChemMedChem
Volume18
Issue number16
DOIs
StatePublished - Aug 15 2023
Externally publishedYes

Keywords

  • adamantyl amine
  • electrophysiology
  • molecular dynamics
  • mutant influenza A M2 proton channel
  • solid-state NMR

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Pharmacology
  • Drug Discovery
  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Organic Chemistry

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