Blockage of HIV-1 replication by flavopiridol mediated inhibition of P-TEFb.
Int Conf AIDS 2000 Jul 9-14; 13:39 (abstract no.. LbPeA7030)
Price D, Chao SH, Fujinaga K, Marion J, Taube R, Sausville E, Senderowicz A, Peterlin M University of Iowa, Department of Biochemistry, Iowa City 52242. Fax: 319-335-9570, E-mail: david-price@uiowa.edu.
Flavopiridol (L86-8275, HMR1275) is a cyclin-dependent kinase (Cdk) inhibitor that is used in clinical trials as a cancer treatment because of its antiproliferative properties. We found that the flavonoid inhibited the kinase activity of P-TEFb with a Ki of 3 nM and was not competitive with ATP. P-TEFb comprised of Cdk9 and cyclin T1 is a required cellular cofactor for the human immuno-deficiency virus (HIV-1). Consistent with its ability to inhibit P-TEFb, flavopiridol blocked Tat transactivation of the viral promoter in vitro. Significantly, flavopiridol blocked HIV-1 replication in both single round and viral spread assays with an IC50 of less than 10 nM. These data suggest that flavopiridol should be evaluated as a therapeutic agent against AIDS.
Keywords: AEGIS, Virus Replication, HIV-1, Flavonoids, Piperidines, Cyclin-Dependent Kinases, Cyclins, Trans-Activation (Genetics), Promoter Regions (Genetics), Antineoplastic Agents, flavopiridol, cyclin T, Human, In Vitro, chemical synthesis, virology, genetics, AIDS
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