Title | Exploring the size limit of templates for inhibitors of the M2 ion channel of influenza A virus |
Publication Type | Journal Article |
Year of Publication | 2011 |
Authors | Duque, MD, Ma C, Torres E, Wang J, Naesens L, Juarez-Jimenez J, Camps P, Luque FJ, DeGrado WF, Lamb RA, Pinto LH, Vazquez S |
Journal | Journal of medicinal chemistry |
Volume | 54 |
Issue | 8 |
Pagination | 2646 - 2657 |
Date Published | 2011/04/28/ |
Keywords | Amantadine/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 |
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. |