TY - JOUR
T1 - Characterization of inhibition of M2 ion channel activity by BL-1743, an inhibitor of influenza A virus
AU - Tu, Qiang
AU - Pinto, Lawrence H.
AU - Luo, Guangxiang
AU - Shaughnessy, Margaret A.
AU - Mullaney, David
AU - Kurtz, Stephen
AU - Krystal, Mark
AU - Lamb, Robert A.
PY - 1996
Y1 - 1996
N2 - 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.
AB - 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.
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U2 - 10.1128/jvi.70.7.4246-4252.1996
DO - 10.1128/jvi.70.7.4246-4252.1996
M3 - Article
C2 - 8676445
AN - SCOPUS:0029665753
SN - 0022-538X
VL - 70
SP - 4246
EP - 4252
JO - Journal of Virology
JF - Journal of Virology
IS - 7
ER -