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

Konstantin H Müller, Denis E Kainov, Karim El Bakkouri UGent, Xavier Saelens UGent, Jef K De Brabander, Christian Kittel, Elisabeth Samm and Claude P Muller (2011) BRITISH JOURNAL OF PHARMACOLOGY. 164(2). p.344-357
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.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
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
journal title
BRITISH JOURNAL OF PHARMACOLOGY
Br. J. Pharmacol.
volume
164
issue
2
pages
344 - 357
Web of Science type
Article
Web of Science id
000294128500016
JCR category
PHARMACOLOGY & PHARMACY
JCR impact factor
4.409 (2011)
JCR rank
35/259 (2011)
JCR quartile
1 (2011)
ISSN
0007-1188
DOI
10.1111/j.1476-5381.2011.01346.x
language
English
UGent publication?
yes
classification
A1
copyright statement
I have transferred the copyright for this publication to the publisher
id
1901516
handle
http://hdl.handle.net/1854/LU-1901516
date created
2011-09-14 17:17:34
date last changed
2016-12-19 15:41:56
@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},
}

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.