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

(2011) BRITISH JOURNAL OF PHARMACOLOGY. 164(2). p.344-357
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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.
Keywords
CONCANAMYCIN-A, BAFILOMYCIN A1, DENGUE VIRUS, BINDING-SITE, H+-ATPASE, concanamycin A, H5N1, pandemic H1N1, influenza A virus, v-ATPase inhibitor, v-ATPase, V-ATPASE, HOST FACTORS, SUBUNIT-C, MEMBRANE-FUSION, bafilomycin A1, archazolid B, salicylihalamide A derivatives, saliphenylhalamide, WEST-NILE-VIRUS

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Citation

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Chicago
Müller, Konstantin H, Denis E Kainov, Karim El Bakkouri, Xavier Saelens, Jef K De Brabander, Christian Kittel, Elisabeth Samm, and Claude P Muller. 2011. “The Proton Translocation Domain of Cellular Vacuolar ATPase Provides a Target for the Treatment of Influenza A Virus Infections.” British Journal of Pharmacology 164 (2): 344–357.
APA
Müller, K. H., Kainov, D. E., El Bakkouri, K., Saelens, X., De Brabander, J. K., Kittel, C., Samm, E., et al. (2011). The proton translocation domain of cellular vacuolar ATPase provides a target for the treatment of influenza A virus infections. BRITISH JOURNAL OF PHARMACOLOGY, 164(2), 344–357.
Vancouver
1.
Müller KH, Kainov DE, El Bakkouri K, Saelens X, De Brabander JK, Kittel C, et al. The proton translocation domain of cellular vacuolar ATPase provides a target for the treatment of influenza A virus infections. BRITISH JOURNAL OF PHARMACOLOGY. 2011;164(2):344–57.
MLA
Müller, Konstantin H, Denis E Kainov, Karim El Bakkouri, et al. “The Proton Translocation Domain of Cellular Vacuolar ATPase Provides a Target for the Treatment of Influenza A Virus Infections.” BRITISH JOURNAL OF PHARMACOLOGY 164.2 (2011): 344–357. Print.
@article{1901516,
  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 {\textlangle} 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.},
  author       = {M{\"u}ller, Konstantin H and Kainov, Denis E and El Bakkouri, Karim and Saelens, Xavier and De Brabander, Jef K and Kittel, Christian and Samm, Elisabeth and Muller, Claude P},
  issn         = {0007-1188},
  journal      = {BRITISH JOURNAL OF PHARMACOLOGY},
  keyword      = {CONCANAMYCIN-A,BAFILOMYCIN A1,DENGUE VIRUS,BINDING-SITE,H+-ATPASE,concanamycin A,H5N1,pandemic H1N1,influenza A virus,v-ATPase inhibitor,v-ATPase,V-ATPASE,HOST FACTORS,SUBUNIT-C,MEMBRANE-FUSION,bafilomycin A1,archazolid B,salicylihalamide A derivatives,saliphenylhalamide,WEST-NILE-VIRUS},
  language     = {eng},
  number       = {2},
  pages        = {344--357},
  title        = {The proton translocation domain of cellular vacuolar ATPase provides a target for the treatment of influenza A virus infections},
  url          = {http://dx.doi.org/10.1111/j.1476-5381.2011.01346.x},
  volume       = {164},
  year         = {2011},
}

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