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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
Summary
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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