Article (Scientific journals)
Synthesis and structure–activity relationships of small molecule inhibitors of the simian virus 40 T antigen oncoprotein, an anti-polyomaviral target
Ireland, Alex W.; Gobillot, Theodore A.; Gupta, Tushar et al.
2014In Bioorganic and Medicinal Chemistry, 22 (22), p. 6490-6502
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Keywords :
SV40 Polyomavirus Large T antigen Viral replication Molecular chaperone Pyrimidinone ATPase
Abstract :
[en] Polyomavirus infections are common and relatively benign in the general human population but can become pathogenic in immunosuppressed patients. Because most treatments for polyomavirus-associated diseases nonspecifically target DNA replication, existing treatments for polyomavirus infection possess undesirable side effects. However, all polyomaviruses express Large Tumor Antigen (T Ag), which is unique to this virus family and may serve as a therapeutic target. Previous screening of pyrimidinone–peptoid hybrid compounds identified MAL2-11B and a MAL2-11B tetrazole derivative as inhibitors of viral replication and T Ag ATPase activity (IC50 of ∼20–50 μM). To improve upon this scaffold and to develop a structure–activity relationship for this new class of antiviral agents, several iterative series of MAL2-11B derivatives were synthesized. The replacement of a flexible methylene chain linker with a benzyl group or, alternatively, the addition of an ortho-methyl substituent on the biphenyl side chain in MAL2-11B yielded an IC50 of ∼50 μM, which retained antiviral activity. After combining both structural motifs, a new lead compound was identified that inhibited T Ag ATPase activity with an IC50 of ∼5 μM. We suggest that the knowledge gained from the structure–activity relationship and a further refinement cycle of the MAL2-11B scaffold will provide a specific, novel therapeutic treatment option for polyomavirus infections and their associated diseases.
Disciplines :
Pharmacy, pharmacology & toxicology
Chemistry
Biochemistry, biophysics & molecular biology
Author, co-author :
Ireland, Alex W.
Gobillot, Theodore A.
Gupta, Tushar
Seguin, Sandlin P.
Liang, Mary
Resnick, Lynn
Goldberg, Margot T.
Manos-Turvey, Alexandra ;  University of Pittsburgh > Department of Biological Sciences and Department of Chemistry
Pipas, James M.
Wipf, Peter
Brodsky, Jeffrey L.
Language :
English
Title :
Synthesis and structure–activity relationships of small molecule inhibitors of the simian virus 40 T antigen oncoprotein, an anti-polyomaviral target
Publication date :
2014
Journal title :
Bioorganic and Medicinal Chemistry
ISSN :
0968-0896
eISSN :
1464-3391
Publisher :
Elsevier Science, Oxford, United Kingdom
Volume :
22
Issue :
22
Pages :
6490-6502
Peer reviewed :
Peer Reviewed verified by ORBi
Available on ORBi :
since 03 June 2016

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