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Flavopiridol Inhibits P-TEFb and Blocks HIV-1 Replication
Journal article   Open access   Peer reviewed

Flavopiridol Inhibits P-TEFb and Blocks HIV-1 Replication

Sheng-Hao Chao, Koh Fujinaga, Jon E Marion, Ran Taube, Edward A Sausville, Adrian M Senderowicz, B. Matija Peterlin and David H Price
The Journal of biological chemistry, Vol.275(37), pp.28345-28348
09/15/2000
DOI: 10.1074/jbc.C000446200
PMID: 10906320
url
https://doi.org/10.1074/jbc.C000446200View
Published (Version of record) Open Access

Abstract

Flavopiridol (L86-8275, HMR1275) is a cyclin-dependent kinase (Cdk) inhibitor that is in clinical trials as a cancer treatment because of its antiproliferative properties. We found that the flavonoid potently inhibited transcription by RNA polymerase II in vitro by blocking the transition into productive elongation, a step controlled by P-TEFb. The ability of P-TEFb to phosphorylate the carboxyl-terminal domain of the large subunit of RNA polymerase II was inhibited by flavopiridol with a K(i) of 3 nm. Interestingly, the drug was not competitive with ATP. P-TEFb composed of Cdk9 and cyclin T1 is a required cellular cofactor for the human immunodeficiency virus (HIV-1) transactivator, Tat. Consistent with its ability to inhibit P-TEFb, flavopiridol blocked Tat transactivation of the viral promoter in vitro. Furthermore, flavopiridol blocked HIV-1 replication in both single-round and viral spread assays with an IC(50) of less than 10 nm.

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