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Inhibition of Simian Virus 40 replication by targeting the molecular chaperone function and ATPase activity of T antigen

Wright, CM and Seguin, SP and Fewell, SW and Zhang, H and Ishwad, C and Vats, A and Lingwood, CA and Wipf, P and Fanning, E and Pipas, JM and Brodsky, JL (2009) Inhibition of Simian Virus 40 replication by targeting the molecular chaperone function and ATPase activity of T antigen. Virus Research, 141 (1). 71 - 80. ISSN 0168-1702

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Abstract

Polyomaviruses such as BK virus and JC virus have been linked to several diseases, but treatments that thwart their propagation are limited in part because of slow growth and cumbersome culturing conditions. In contrast, the replication of one member of this family, Simian Virus 40 (SV40), is robust and has been well-characterized. SV40 replication requires two domains within the viral-encoded large tumor antigen (TAg): The ATPase domain and the N-terminal J domain, which stimulates the ATPase activity of the Hsp70 chaperone. To assess whether inhibitors of polyomavirus replication could be identified, we examined a recently described library of small molecules, some of which inhibit chaperone function. One compound, MAL2-11B, inhibited both TAg's endogenous ATPase activity and the TAg-mediated activation of Hsp70. MAL2-11B also reduced SV40 propagation in plaque assays and compromised DNA replication in cell culture and in vitro. Furthermore, the compound significantly reduced the growth of BK virus in a human kidney cell line. These data indicate that pharmacological inhibition of TAg's chaperone and ATPase activities may provide a route to combat polyomavirus-mediated disease. © 2009 Elsevier B.V. All rights reserved.

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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Wright, CM
Seguin, SP
Fewell, SW
Zhang, H
Ishwad, C
Vats, A
Lingwood, CA
Wipf, Ppwipf@pitt.eduPWIPF
Fanning, E
Pipas, JMpipas@pitt.eduPIPAS
Brodsky, JLjbrodsky@pitt.eduJBRODSKY0000-0002-6984-8486
Date: 1 April 2009
Date Type: Publication
Journal or Publication Title: Virus Research
Volume: 141
Number: 1
Page Range: 71 - 80
DOI or Unique Handle: 10.1016/j.virusres.2008.12.018
Schools and Programs: Dietrich School of Arts and Sciences > Chemistry
Refereed: Yes
ISSN: 0168-1702
MeSH Headings: Adenosine Triphosphatases--genetics; Adenosine Triphosphatases--metabolism; Antigens, Viral, Tumor--genetics; Antigens, Viral, Tumor--metabolism; Cell Line; Down-Regulation; HSP70 Heat-Shock Proteins--genetics; HSP70 Heat-Shock Proteins--metabolism; Humans; Simian virus 40--drug effects; Simian virus 40--genetics; Simian virus 40--physiology; Small Molecule Libraries--pharmacology; Viral Proteins--genetics; Viral Proteins--metabolism; Virus Replication--drug effects
Other ID: NLM NIHMS132836, NLM PMC2758074
PubMed Central ID: PMC2758074
PubMed ID: 19200446
Date Deposited: 18 Jun 2013 20:33
Last Modified: 02 Feb 2019 15:57
URI: http://d-scholarship.pitt.edu/id/eprint/19039

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