Flavopiridol Inhibits P-TEFb and Blocks HIV-1 Replication

作者：Sheng‐Hao Chao, Koh Fujinaga, Jon E. Marion, Ran Taube, Edward A. Sausville, Adrian Mario Senderowicz, Boris Matija Peterlin, David H.R. Price · 发表于：Journal of Biological Chemistry · 年份：2000 · DOI：10.1074/jbc.c000446200 · 被引用次数：467 · 研究领域：HIV Research and Treatment、HIV/AIDS drug development and treatment、Cancer-related Molecular Pathways

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.