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Br J Pharmacol. 2011 Sep;164(2):344-57. doi: 10.1111/j.1476-5381.2011.01346.x.

The proton translocation domain of cellular vacuolar ATPase provides a target for the treatment of influenza A virus infections.

Author information

1
Institute of Immunology, Centre de Recherche Public-Santé/Laboratoire National de Santé, Luxembourg, Luxembourg. Claude.Muller@LNS.ETAT.LU

Abstract

BACKGROUND AND PURPOSE:

Cellular vacuolar ATPases (v-ATPase) play an important role in endosomal acidification, a critical step in influenza A virus (IAV) host cell infection. We investigated the antiviral activity of the v-ATPase inhibitor saliphenylhalamide (SaliPhe) and compared it with several older v-ATPase inhibitors concanamycin A, bafilomycin A1, (BafA) and archazolid B targeting the subunit c of the V(0) sector.

EXPERIMENTAL APPROACH:

An in vitro assay was devised to quantify the anti-influenza effect of v-ATPase inhibitors by measuring green fluorescent protein fluorescence of a reporter IAV. These data were combined with cytotoxicity testing to calculate selectivity indices. Data were validated by testing v-ATPase inhibitors against wild-type IAV in vitro and in vivo in mice.

KEY RESULTS:

In vitro SaliPhe blocked the proliferation of pandemic and multidrug resistant viruses at concentrations up to 51-fold below its cytotoxic concentrations. At essentially non-toxic concentrations, SaliPhe protected 62.5% of mice against a lethal challenge of a mouse-adapted influenza strain, while BafA at cytotoxic concentrations showed essentially no protection against infection with IAV (SaliPhe vs. BafA P < 0.001).

CONCLUSIONS AND IMPLICATIONS:

Our results show that a distinct binding site of the proton translocation domain of cellular v-ATPase can be selectively targeted by a new generation v-ATPase inhibitor with reduced toxicity to treat influenza virus infections, including multi-resistant strains. Treatment strategies against influenza that target host cellular proteins are expected to be more resistant to virus mutations than drugs blocking viral proteins.

PMID:
21418188
PMCID:
PMC3174415
DOI:
10.1111/j.1476-5381.2011.01346.x
[Indexed for MEDLINE]
Free PMC Article

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