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A screen for modulators of large T antigen's ATPase activity uncovers novel inhibitors of Simian Virus 40 and BK virus replication

Seguin, SP and Ireland, AW and Gupta, T and Wright, CM and Miyata, Y and Wipf, P and Pipas, JM and Gestwicki, JE and Brodsky, JL (2012) A screen for modulators of large T antigen's ATPase activity uncovers novel inhibitors of Simian Virus 40 and BK virus replication. Antiviral Research, 96 (1). 70 - 81. ISSN 0166-3542

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Abstract

New polyomaviruses are continually being identified, and it is likely that links between this virus family and disease will continue to emerge. Unfortunately, a specific treatment for polyomavirus-associated disease is lacking. Because polyomaviruses express large Tumor Antigen, TAg, we hypothesized that small molecule inhibitors of the essential ATPase activity of TAg would inhibit viral replication. Using a new screening platform, we identified inhibitors of TAg's ATPase activity. Lead compounds were moved into a secondary assay, and ultimately two FDA approved compounds, bithionol and hexachlorophene, were identified as the most potent TAg inhibitors known to date. Both compounds inhibited Simian Virus 40 replication as assessed by plaque assay and quantitative PCR. Moreover, these compounds inhibited BK virus, which causes BKV Associated Nephropathy. In neither case was host cell viability compromised at these concentrations. Our data indicate that directed screening for TAg inhibitors is a viable method to identify polyomavirus inhibitors, and that bithionol and hexachlorophene represent lead compounds that may be further modified and/or ultimately used to combat diseases associated with polyomavirus infection. © 2012 Elsevier B.V.


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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Seguin, SP
Ireland, AW
Gupta, T
Wright, CM
Miyata, Y
Wipf, Ppwipf@pitt.eduPWIPF
Pipas, JMpipas@pitt.eduPIPAS
Gestwicki, JE
Brodsky, JLjbrodsky@pitt.eduJBRODSKY0000-0002-6984-8486
Date: 1 October 2012
Date Type: Publication
Journal or Publication Title: Antiviral Research
Volume: 96
Number: 1
Page Range: 70 - 81
DOI or Unique Handle: 10.1016/j.antiviral.2012.07.012
Schools and Programs: Dietrich School of Arts and Sciences > Chemistry
Refereed: Yes
ISSN: 0166-3542
MeSH Headings: Adenosine Triphosphatases--antagonists & inhibitors; Antigens, Viral, Tumor--metabolism; Antiviral Agents--isolation & purification; Antiviral Agents--pharmacology; BK Virus--drug effects; BK Virus--enzymology; BK Virus--physiology; Drug Evaluation, Preclinical--methods; Enzyme Inhibitors--isolation & purification; Enzyme Inhibitors--pharmacology; Humans; Real-Time Polymerase Chain Reaction; Simian virus 40--drug effects; Simian virus 40--enzymology; Simian virus 40--physiology; Viral Plaque Assay; Virus Replication--drug effects
Other ID: NLM NIHMS400070 [Available on 10/01/13], NLM PMC3465505 [Available on 10/01/13]
PubMed Central ID: PMC3465505
PubMed ID: 22898086
Date Deposited: 14 May 2013 14:55
Last Modified: 02 Feb 2019 15:56
URI: http://d-scholarship.pitt.edu/id/eprint/18715

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