title: Identification of flavopiridol analogues that selectively inhibit positive transcription elongation factor (P-TEFb) and block HIV-1 replication.
abstract: 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.
authors: Chemical Biology Program, Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01605 (USA).
authors: Akbar
authors: A
authors: Ali
authors: Animesh
authors: A
authors: Ghosh
authors: Robin S
authors: RS
authors: Nathans
authors: Natalia
authors: N
authors: Sharova
authors: Siobhan
authors: S
authors: O'Brien
authors: Hong
authors: H
authors: Cao
authors: Mario
authors: M
authors: Stevenson
authors: Tariq M
authors: TM
authors: Rana
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D005419:Flavonoids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects* / Q000254:growth & development*; D006367:HeLa Cells; D006801:Humans; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D042925:Positive Transcriptional Elongation Factor B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D019380:Anti-HIV Agents; D005419:Flavonoids; D010880:Piperidines; C077990:alvocidib; D042925:Positive Transcriptional Elongation Factor B