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Identification of Flavopiridol Analogues that Selectively Inhibit Positive Transcription Elongation Factor (P‐TEFb) and Block HIV‐1 Replication
Author(s) -
Ali Akbar,
Ghosh Animesh,
Nathans Robin S.,
Sharova Natalia,
O'Brien Siobhan,
Cao Hong,
Stevenson Mario,
Rana Tariq M.
Publication year - 2009
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.200900303
Subject(s) - p tefb , transactivation , cyclin dependent kinase , biology , cyclin dependent kinase 9 , microbiology and biotechnology , rna polymerase ii , kinase , transcription factor , chemistry , cyclin dependent kinase 2 , biochemistry , gene expression , gene , cell cycle , protein kinase a , promoter
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.