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American Chemical Society, Journal of Medicinal Chemistry, 8(54), p. 2646-2657, 2011

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

Journal article published in 2011 by María D. Duque, Chunlong, Chunlong Ma, Eva Torres, Jun Wang, Lieve Naesens, Jordi Juárez-Jiménez, Pelayo Camps ORCID, F. Javier Luque, F. Javier Luque ORCID, William F. DeGrado, Robert A. Lamb, Lawrence H. Pinto, Santiago Vázquez
This paper is available in a repository.
This paper is available in a repository.

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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.