Exploring the Size Limit of Templates for Inhibitors of the M2 Ion Channel of Influenza A Virus

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• 作者：Mari虂a D. Duque ; Chunlong Ma ; Eva Torres ; Jun Wang ; Lieve Naesens ; Jordi Jua虂rez-Jime虂nez ; Pelayo Camps ; F. Javier Luque ; William F. DeGrado ; Robert A. Lamb ; Lawrence H. Pinto ; Santiago Va虂zquez
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：April 28, 2011
• 年：2011
• 卷：54
• 期：8
• 页码：2646-2657
• 全文大小：1058K
• 年卷期：v.54,no.8(April 28, 2011)
• ISSN：1520-4804

文摘

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鈭抋ctivity relationship obtained by TEV assay was confirmed by plaque reduction assays with A/H3N2 influenza virus carrying wt M2 protein.