Hsu M C, Schutt A D, Holly M, Slice L W, Sherman M I, Richman D D, Potash M J, Volsky D J
Department of Virology, Hoffmann-La Roche, Nutley, NJ 07110.
Science. 1991 Dec 20;254(5039):1799-802. doi: 10.1126/science.1763331.
The human immunodeficiency virus-1 (HIV-1) trans-activator Tat is an attractive target for the development of antiviral drugs because inhibition of Tat would arrest the virus at an early stage. The drug Ro 5-3335 [7-chloro-5-(2-pyrryl)-3H-1,4-benzodiazepine-2(H)-one], inhibited gene expression by HIV-1 at the level of transcriptional trans-activation by Tat. The compound did not inhibit the basal activity of the promoter. Both Tat and its target sequence TAR were required for the observed inhibitory activity. Ro 5-3335 reduced the amount of cell-associated viral RNA and antigen in acutely, as well as in chronically infected cells in vitro (median inhibition concentration 0.1 to 1 micromolar). Effective inhibition of viral replication was also observed 24 hours after cells were transfected with infectious recombinant HIV-1 DNA. The compound was active against both HIV-1 and HIV-2 and against 3'-azido-3'-deoxythymidine (AZT)-resistant clinical isolates.
人类免疫缺陷病毒1型（HIV-1）反式激活因子Tat是开发抗病毒药物的一个有吸引力的靶点，因为抑制Tat可在病毒早期阶段阻止其复制。药物Ro 5-3335 [7-氯-5-（2-吡咯基）-3H-1,4-苯并二氮杂卓-2(H)-酮] 在Tat介导的转录反式激活水平上抑制HIV-1的基因表达。该化合物不抑制启动子的基础活性。观察到的抑制活性需要Tat及其靶序列TAR。Ro 5-3335在体外可减少急性感染以及慢性感染细胞中与细胞相关的病毒RNA和抗原的量（中位抑制浓度为0.1至1微摩尔）。在用感染性重组HIV-1 DNA转染细胞24小时后，也观察到对病毒复制的有效抑制。该化合物对HIV-1和HIV-2以及对3'-叠氮-3'-脱氧胸苷（AZT）耐药的临床分离株均有活性。
