Inhibition of Simian Virus 40 replication by targeting the molecular chaperone function and ATPase activity of T antigen.
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.
Wright
Christine M
CM
Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA 15260, USA.
Seguin
Sandlin P
SP
Fewell
Sheara W
SW
Zhang
Haijiang
H
Ishwad
Chandra
C
Vats
Abhay
A
Lingwood
Clifford A
CA
Wipf
Peter
P
Fanning
Ellen
E
Pipas
James M
JM
Brodsky
Jeffrey L
JL
D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism*; D000957:Antigens, Viral, Tumor / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D015536:Down-Regulation; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D013539:Simian virus 40 / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D054852:Small Molecule Libraries / Q000494:pharmacology*; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*; D014779:Virus Replication / Q000187:drug effects*
D000957:Antigens, Viral, Tumor; D018840:HSP70 Heat-Shock Proteins; D054852:Small Molecule Libraries; D014764:Viral Proteins; D000251:Adenosine Triphosphatases