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

TitleExploring the size limit of templates for inhibitors of the M2 ion channel of influenza A virus
Publication TypeJournal Article
Year of Publication2011
AuthorsDuque, MD, Ma C, Torres E, Wang J, Naesens L, Juarez-Jimenez J, Camps P, Luque FJ, DeGrado WF, Lamb RA, Pinto LH, Vazquez S
JournalJournal of medicinal chemistry
Pagination2646 - 2657
Date Published2011/04/28/
KeywordsAmantadine/chemistry/pharmacology; Animals; Antiviral Agents/chemistry/pharmacology; Cell Line; Dogs; Influenza A virus/drug effects/growth & development; Magnetic Resonance Spectroscopy; Models, Infrared; Structure-Activity Relationship; Viral Matrix Proteins/antagonists & inhibitors/chemistry; Xenopus, Molecular; Patch-Clamp Techniques; Plaque Assay; Spectrophotometry
AbstractAmantadine 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.