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


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.

SUBMITTER: Duque MD 

PROVIDER: S-EPMC3174104 | biostudies-literature | 2011 Apr

REPOSITORIES: biostudies-literature

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

Duque María D MD   Ma Chunlong C   Torres Eva E   Wang Jun J   Naesens Lieve L   Juárez-Jiménez Jordi J   Camps Pelayo P   Luque F Javier FJ   DeGrado William F WF   Lamb Robert A RA   Pinto Lawrence H LH   Vázquez Santiago S  

Journal of medicinal chemistry 20110405 8


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 bisnoradam  ...[more]

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