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

María D. Duque, Chunlong Ma, Eva Torres, Jun Wang, Lieve Naesens, Jordi Juárez-Jiménez, Pelayo Camps, F. Javier Luque, William F. Degrado, Robert A. Lamb, Lawrence H. Pinto, Santiago Vázquez

Research output: Contribution to journalArticle

56 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2646-2657
Number of pages12
JournalJournal of Medicinal Chemistry
Volume54
Issue number8
DOIs
StatePublished - Apr 28 2011

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Fingerprint Dive into the research topics of 'Exploring the size limit of templates for inhibitors of the M2 ion channel of influenza A virus'. Together they form a unique fingerprint.

  • Cite this

    Duque, M. D., Ma, C., Torres, E., Wang, J., Naesens, L., Juárez-Jiménez, J., Camps, P., Luque, F. J., Degrado, W. F., Lamb, R. A., Pinto, L. H., & Vázquez, S. (2011). Exploring the size limit of templates for inhibitors of the M2 ion channel of influenza A virus. Journal of Medicinal Chemistry, 54(8), 2646-2657. https://doi.org/10.1021/jm101334y