Debyser Z, Pauwels R, Andries K, Desmyter J, Kukla M, Janssen P A, De Clercq E
Rega Institute for Medical Research, Katholieke Universiteit Leuven, Belgium.
Proc Natl Acad Sci U S A. 1991 Feb 15;88(4):1451-5. doi: 10.1073/pnas.88.4.1451.
Screening of pharmacologically acceptable prototype compounds has recently led to the discovery of a series of ultraselective inhibitors of human immunodeficiency virus (HIV)-1 replication, the tetrahydroimidazo[4,5,1-jk] [1,4]-benzodiazepin-2(1H)-one and -thione (TIBO) derivatives. The TIBO compounds completely suppress the formation of proviral DNA in acutely infected cells, as revealed by polymerase chain reaction (PCR) analysis. TIBO derivatives are inhibitory to the reverse transcriptase (RT) of HIV-1 but not that of HIV-2 or other retroviruses. The inhibition is most effective with poly(C)-oligo(dG) as the template/primer, and it is selectively directed against the RNA-dependent DNA polymerase activity and not the accompanying DNA-dependent DNA polymerase and ribonuclease H activity of HIV-1 RT. Kinetic studies point to an uncompetitive inhibition with regard to the template/primer. TIBO compounds are active against HIV-1 replication through a unique interaction with HIV-1 RT. The experimental data indicate the existence of a target on HIV-1 RT that is responsible for the inhibition of replication and a mode of action unrelated to that of previously studied RT inhibitors.
最近，对药理学上可接受的原型化合物进行筛选，发现了一系列超选择性抑制人类免疫缺陷病毒（HIV）-1复制的化合物，即四氢咪唑并[4,5,1-jk][1,4]-苯并二氮杂䓬-2(1H)-酮和硫酮（TIBO）衍生物。聚合酶链反应（PCR）分析显示，TIBO化合物能完全抑制急性感染细胞中前病毒DNA的形成。TIBO衍生物对HIV-1的逆转录酶（RT）有抑制作用，但对HIV-2或其他逆转录病毒的RT无抑制作用。以聚（C）-寡聚（dG）作为模板/引物时，这种抑制作用最为有效，并且它选择性地针对RNA依赖性DNA聚合酶活性，而不是HIV-1 RT伴随的DNA依赖性DNA聚合酶和核糖核酸酶H活性。动力学研究表明，对于模板/引物而言，这是一种非竞争性抑制。TIBO化合物通过与HIV-1 RT的独特相互作用，对HIV-1复制具有活性。实验数据表明，HIV-1 RT上存在一个负责抑制复制的靶点，其作用方式与先前研究的RT抑制剂不同。
