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

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.

• Authors: Konstantin H Müller, Denis E Kainov, Karim El Bakkouri, Xavier Saelens, Jef K De Brabander, Christian Kittel, Elisabeth Samm, Claude P Muller
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 164 Issue 2 Pg. 344-57 (Sep 2011) ISSN: 1476-5381 [Electronic] England
• PMID: 21418188 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.

Chemical References

• Antiviral Agents
• Enzyme Inhibitors
• Green Fluorescent Proteins
• Vacuolar Proton-Translocating ATPases

Topics

• Animals
• Antiviral Agents (chemistry, pharmacology)
• Cell Line
• Dogs
• Enzyme Inhibitors (chemistry, pharmacology)
• Green Fluorescent Proteins (metabolism)
• Influenza A Virus, H1N1 Subtype
• Mice
• Mice, Inbred BALB C
• Molecular Structure
• Orthomyxoviridae Infections (drug therapy, virology)
• Protein Structure, Tertiary
• Time Factors
• Vacuolar Proton-Translocating ATPases (antagonists & inhibitors, metabolism)
• Virus Replication (drug effects)