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XB-ART-43042
J Med Chem 2011 Apr 28;548:2646-57. doi: 10.1021/jm101334y.
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Exploring the size limit of templates for inhibitors of the M2 ion channel of influenza A virus.

Duque MD , Ma C , Torres E , Wang J , Naesens L , Juárez-Jiménez J , Camps P , Luque FJ , DeGrado WF , Lamb RA , Pinto LH , Vázquez S .


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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.

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References [+] :
Acharya, Structure and mechanism of proton transport through the transmembrane tetrameric M2 protein bundle of the influenza A virus. 2010, Pubmed, Xenbase