A screen for modulators of large T antigen's ATPase activity uncovers novel inhibitors of Simian Virus 40 and BK virus replication.
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.
Department of Biological Science, University of Pittsburgh, Pittsburgh, PA 15260, USA.
Sandlin P
SP
Seguin
Alex W
AW
Ireland
Tushar
T
Gupta
Christine M
CM
Wright
Yoshinari
Y
Miyata
Peter
P
Wipf
James M
JM
Pipas
Jason E
JE
Gestwicki
Jeffrey L
JL
Brodsky
D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors*; D000957:Antigens, Viral, Tumor / Q000378:metabolism*; D000998:Antiviral Agents / Q000302:isolation & purification / Q000494:pharmacology*; D001739:BK Virus / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004791:Enzyme Inhibitors / Q000302:isolation & purification / Q000494:pharmacology*; D006801:Humans; D060888:Real-Time Polymerase Chain Reaction; D013539:Simian virus 40 / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology; D010948:Viral Plaque Assay; D014779:Virus Replication / Q000187:drug effects*
D000957:Antigens, Viral, Tumor; D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D000251:Adenosine Triphosphatases