Identification of flavopiridol analogues that selectively inhibit positive transcription elongation factor (P-TEFb) and block HIV-1 replication

Akbar Ali, Animesh Ghosh, Robins S. Nathans, Natalia Sharova, Siobhan O'Brien, Hong Cao, Mario Stevenson, Tariq M. Rana

Research output: Contribution to journalArticle

35 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2072-2080
Number of pages9
JournalChemBioChem
Volume10
Issue number12
DOIs
StatePublished - Aug 17 2009
Externally publishedYes

Keywords

  • Antiviral agents
  • Cyclin-dependent kinases
  • Enzymes
  • Inhibitors
  • P-TEFb

ASJC Scopus subject areas

  • Biochemistry
  • Organic Chemistry
  • Molecular Medicine
  • Molecular Biology

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