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: |
|
| 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-dev.library.pitt.edu/id/eprint/18715 |
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