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Flavopiridol inhibits P-TEFb and blocks HIV-1 replication

S H Chao1, K Fujinaga, J E Marion

  • 1Molecular Biology Program and the Department of Biochemistry, University of Iowa, Iowa City, Iowa 52242, USA.

The Journal of Biological Chemistry
|July 25, 2000
PubMed

Insights

Flavopiridol effectively inhibits RNA polymerase II transcription and HIV-1 replication by targeting P-TEFb. This cyclin-dependent kinase inhibitor shows potent antiviral and antiproliferative activity in vitro.

Area of Science:

  • Molecular Biology
  • Virology
  • Pharmacology

Background:

  • Flavopiridol is a cyclin-dependent kinase (Cdk) inhibitor investigated for cancer treatment due to its antiproliferative effects.
  • Transcription by RNA polymerase II is a critical process regulated by factors like P-TEFb.

Purpose of the Study:

  • To investigate the mechanism by which flavopiridol inhibits transcription.
  • To evaluate the effect of flavopiridol on human immunodeficiency virus type 1 (HIV-1) replication.

Main Methods:

  • In vitro transcription assays using RNA polymerase II.
  • Enzyme inhibition studies to determine the binding kinetics of flavopiridol to P-TEFb.
  • HIV-1 replication assays (single-round and viral spread).

Main Results:

  • Flavopiridol potently inhibited RNA polymerase II transcription by blocking the transition to productive elongation, a step mediated by P-TEFb.
  • The drug inhibited P-TEFb's ability to phosphorylate the RNA polymerase II carboxyl-terminal domain with a K(i) of 3 nm, non-competitively with ATP.
  • Flavopiridol blocked Tat transactivation of the HIV-1 promoter and inhibited HIV-1 replication with an IC(50) < 10 nm.

Conclusions:

  • Flavopiridol is a potent inhibitor of P-TEFb and RNA polymerase II transcription.
  • Flavopiridol demonstrates significant antiviral activity against HIV-1 by inhibiting viral replication.

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