Characterization of inhibition of M2 ion channel activity by BL-1743, an inhibitor of influenza A virus

Qiang Tu, Lawrence H. Pinto, Guangxiang Luo, Margaret A. Shaughnessy, David Mullaney, Stephen Kurtz, Mark Krystal, Robert A. Lamb

Research output: Contribution to journalArticle

43 Scopus citations

Abstract

The influenza A virus M2 integral membrane protein has ion channel activity that can be inhibited by the antiviral drug amantadine. Recently, a spirene-containing compound, BL-1743 {2-[3-azaspiro (5,5)undecanol]-2- imidazoline}, that inhibits influenza virus growth was identified (S. Kurtz, G. Luo, K. M. Hahnenberger, C. Brooks, O. Gecha, K. Ingalls, K.-I. Numata, and M. Krystal, Antimicrob. Agents Chemother. 39:2204-2209, 1995). We have examined the ability of BL-1743 to inhibit the M2 ion channel when expressed in oocytes of Xenopus laevis. BL-1743 inhibition is complete as far as can be measured by electrophysiological methods and is reversible, with a reverse reaction rate constant of 4.0 x 10-3 s-1. In contrast, amantadine inhibition is irreversible within the time frame of the experiment. However, BL-1743 inhibition and amantadine inhibition have similar properties. The majority of isolated influenza viruses resistant to BL-1743 are also amantadine resistant. In addition, all known amino acid changes which result in amantadine resistance also confer BL-1743 resistance. However, one BL- 1743-resistant virus isolated, designated M2-I35T, contained the change Ile-35→Thr. This virus is >70-fold more resistant to BL-1743 and only 10- fold more resistant to amantadine than the wild-type virus. When the ion channel activity of M2-I35T was examined in oocytes, it was found that M2-I35T is BL-1743 resistant but is reversibly inhibited by amantadine. These findings suggest that these two drugs interact differently with the M2 protein transmembrane pure region.

Original languageEnglish (US)
Pages (from-to)4246-4252
Number of pages7
JournalJournal of virology
Volume70
Issue number7
StatePublished - Jun 27 1996

    Fingerprint

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

Cite this

Tu, Q., Pinto, L. H., Luo, G., Shaughnessy, M. A., Mullaney, D., Kurtz, S., Krystal, M., & Lamb, R. A. (1996). Characterization of inhibition of M2 ion channel activity by BL-1743, an inhibitor of influenza A virus. Journal of virology, 70(7), 4246-4252.