Exploring the size limit of templates for inhibitors of the M2 ion channel of influenza A virus

María D. Duque, Chunlong Ma, Eva Torres, Jun Wang, Lieve Naesens, Jordi Juárez-Jiménez, Pelayo Camps, F Javier Luque, William F. Degrado, Robert A. Lamb, Lawrence H. Pinto, Santiago Vázquez*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Amantadine inhibits the M2 proton channel of influenza A virus, yet its clinical use has been limited by the rapid emergence of amantadine-resistant virus strains. We have synthesized and characterized a series of polycyclic compounds designed as ring-contracted or ring-expanded analogues of amantadine. Inhibition of the wild-type (wt) M2 channel and the A/M2-S31N and A/M2-V27A mutant ion channels were measured in Xenopus oocytes using two-electrode voltage clamp (TEV) assays. Several bisnoradamantane and noradamantane derivatives inhibited the wt ion channel. The compounds bind to a primary site delineated by Val27, Ala30, and Ser31, though ring expansion restricts the positioning in the binding site. Only the smallest analogue 8 was found to inhibit the S31N mutant ion channel. The structure-activity relationship obtained by TEV assay was confirmed by plaque reduction assays with A/H3N2 influenza virus carrying wt M2 protein.

Original languageEnglish
Pages (from-to)2646-2657
Number of pages12
JournalJournal of Medicinal Chemistry
Volume54
Issue number8
DOIs
Publication statusPublished - 28 Apr 2011

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