Identification of flavopiridol analogues that selectively inhibit positive transcription elongation factor (P-TEFb) and block HIV-1 replication
Authors
Ali, AkbarGhosh, Animesh
Nathans, Robin S.
Sharova, Natalia
O'Brien, Siobhan
Cao, Hong
Stevenson, Mario
Rana, Tariq M.
UMass Chan Affiliations
Program in Molecular MedicineDepartment of Biochemistry and Molecular Pharmacology
Document Type
Journal ArticlePublication Date
2009-07-16Keywords
Anti-HIV AgentsCell Proliferation
Drug Evaluation, Preclinical
Flavonoids
HIV-1
Hela Cells
Humans
Microbial Sensitivity Tests
Molecular Structure
Piperidines
Positive Transcriptional Elongation Factor B
inhibitors
Virus Replication
Life Sciences
Medicine and Health Sciences
Metadata
Show full item recordAbstract
The positive transcription elongation factor (P-TEFb; CDK9/cyclin T1) regulates RNA polymerase II-dependent transcription of cellular and integrated viral genes. It is an essential cofactor for HIV-1 Tat transactivation, and selective inhibition of P-TEFb blocks HIV-1 replication without affecting cellular transcription; this indicates that P-TEFb could be a potential target for developing anti-HIV-1 therapeutics. Flavopiridol, a small molecule CDK inhibitor, blocks HIV-1 Tat transactivation and viral replication by inhibiting P-TEFb kinase activity, but it is highly cytotoxic. In the search for selective and less cytotoxic P-TEFb inhibitors, we prepared a series of flavopiridol analogues and evaluated their kinase inhibitory activity against P-TEFb and CDK2/cyclin A, and tested their cellular antiviral potency and cytotoxicity. We identified several analogues that selectively inhibit P-TEFb kinase activity in vitro and show antiviral potency comparable to that of flavopiridol, but with significantly reduced cytotoxicity. These compounds are valuable molecular probes for understanding P-TEFb-regulated cellular and HIV-1 gene transcription and provide potential anti-HIV-1 therapeutics.Source
Chembiochem. 2009 Aug 17;10(12):2072-80. Link to article on publisher's site
DOI
10.1002/cbic.200900303Permanent Link to this Item
http://hdl.handle.net/20.500.14038/39318PubMed ID
19603446Related Resources
ae974a485f413a2113503eed53cd6c53
10.1002/cbic.200900303