Identification of Flavopiridol Analogues that Selectively Inhibit Positive Transcription Elongation Factor (P-TEFb) and Block HIV-1 Replication
Identification of Flavopiridol Analogues that Selectively Inhibit Positive Transcription Elongation Factor (P-TEFb) and Block HIV-1 Replication
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DOI：
10.1002/cbic.200900303
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发表时间：
2009-08-17
期刊：
影响因子：
3.2
通讯作者：
Rana, Tariq M.
中科院分区：
文献类型：
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作者：
Ali, Akbar;Ghosh, Animesh;Rana, Tariq M.
正转录延伸因子（P-TEFb; CDK 9/细胞周期蛋白T1）调节RNA聚合酶II依赖的细胞和整合的病毒基因的转录。它是HIV-1达特反式激活的重要辅因子，并且选择性抑制P-TEFb阻断HIV-1复制而不影响细胞转录;这表明P-TEFb可能是开发抗HIV-1治疗剂的潜在靶标。Flavopiridol是一种小分子CDK抑制剂，通过抑制P-TEFb激酶活性来阻断HIV-1达特反式激活和病毒复制，但它具有高度细胞毒性。在寻找选择性和细胞毒性较小的P-TEFb抑制剂的过程中，我们制备了一系列flavopiridol类似物，并评估了它们对P-TEFb和CDK 2/cyclin A的激酶抑制活性，并测试了它们的细胞抗病毒效力和细胞毒性。我们鉴定了几种在体外选择性抑制P-TEFb激酶活性的类似物，其抗病毒效力与flavopiridol相当，但细胞毒性显著降低。这些化合物是用于理解P-TEFb调节的细胞和HIV-1基因转录的有价值的分子探针，并提供潜在的抗HIV-1治疗剂。
The positive transcription elongation factor (P-TEFb; CDK9/cyclin T1) regulates RNA polymerase II-dependent transcription of cellular and integrated viral genes. It is an essential cofactor for HIV-1 Tat transactivation, and selective inhibition of P-TEFb blocks HIV-1 replication without affecting cellular transcription; this indicates that P-TEFb could be a potential target for developing anti-HIV-1 therapeutics. Flavopiridol, a small molecule CDK inhibitor, blocks HIV-1 Tat transactivation and viral replication by inhibiting P-TEFb kinase activity, but it is highly cytotoxic. In the search for selective and less cytotoxic P-TEFb inhibitors, we prepared a series of flavopiridol analogues and evaluated their kinase inhibitory activity against P-TEFb and CDK2/cyclin A, and tested their cellular antiviral potency and cytotoxicity. We identified several analogues that selectively inhibit P-TEFb kinase activity in vitro and show antiviral potency comparable to that of flavopiridol, but with significantly reduced cytotoxicity. These compounds are valuable molecular probes for understanding P-TEFb-regulated cellular and HIV-1 gene transcription and provide potential anti-HIV-1 therapeutics.