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

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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 - 1996
Externally publishedYes

Fingerprint

Influenza A virus
ion channels
Ion Channels
Amantadine
Orthomyxoviridae
viruses
oocytes
antiviral agents
transmembrane proteins
Xenopus laevis
membrane proteins
drugs
Viruses
amino acids
Oocytes
2-(3-azaspiro(5,5)undecanol)-2-imidazoline
Antiviral Agents
methodology
Membrane Proteins
Amino Acids

ASJC Scopus subject areas

  • Immunology

Cite this

Tu, Q., Pinto, L. H., Luo, G., Shaughnessy, M. A., Mullaney, D., Kurtz, S., ... 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.

Characterization of inhibition of M2 ion channel activity by BL-1743, an inhibitor of influenza A virus. / Tu, Qiang; Pinto, Lawrence H.; Luo, Guangxiang; Shaughnessy, Margaret A.; Mullaney, David; Kurtz, Stephen; Krystal, Mark; Lamb, Robert A.

In: Journal of Virology, Vol. 70, No. 7, 1996, p. 4246-4252.

Research output: Contribution to journalArticle

Tu, Q, Pinto, LH, Luo, G, Shaughnessy, MA, Mullaney, D, Kurtz, S, Krystal, M & Lamb, RA 1996, 'Characterization of inhibition of M2 ion channel activity by BL-1743, an inhibitor of influenza A virus', Journal of Virology, vol. 70, no. 7, pp. 4246-4252.
Tu, Qiang ; Pinto, Lawrence H. ; Luo, Guangxiang ; Shaughnessy, Margaret A. ; Mullaney, David ; Kurtz, Stephen ; Krystal, Mark ; Lamb, Robert A. / Characterization of inhibition of M2 ion channel activity by BL-1743, an inhibitor of influenza A virus. In: Journal of Virology. 1996 ; Vol. 70, No. 7. pp. 4246-4252.
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