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 Citations (Scopus)

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

Fingerprint

alvocidib
Positive Transcriptional Elongation Factor B
Transcription
HIV-1
Transcription Factors
Phosphotransferases
Cytotoxicity
Transcriptional Activation
Antiviral Agents
Cyclin T
Genes
Molecular Probes
Cyclin A
Viral Genes
factor EF-P
RNA Polymerase II

Keywords

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

ASJC Scopus subject areas

  • Biochemistry
  • Organic Chemistry
  • Molecular Medicine
  • Molecular Biology

Cite this

Identification of flavopiridol analogues that selectively inhibit positive transcription elongation factor (P-TEFb) and block HIV-1 replication. / Ali, Akbar; Ghosh, Animesh; Nathans, Robins S.; Sharova, Natalia; O'Brien, Siobhan; Cao, Hong; Stevenson, Mario; Rana, Tariq M.

In: ChemBioChem, Vol. 10, No. 12, 17.08.2009, p. 2072-2080.

Research output: Contribution to journalArticle

Ali, Akbar ; Ghosh, Animesh ; Nathans, Robins S. ; Sharova, Natalia ; O'Brien, Siobhan ; Cao, Hong ; Stevenson, Mario ; Rana, Tariq M. / Identification of flavopiridol analogues that selectively inhibit positive transcription elongation factor (P-TEFb) and block HIV-1 replication. In: ChemBioChem. 2009 ; Vol. 10, No. 12. pp. 2072-2080.
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