Debyser Z, De Vreese K, Pauwels R, Yamamoto N, Anné J, De Clercq E, Desmyter J
Rega Institute for Medical Research, Katholieke Universiteit Leuven, Belgium.
J Gen Virol. 1992 Jul;73 ( Pt 7):1799-804. doi: 10.1099/0022-1317-73-7-1799.
Recently, several classes of compounds have been shown to be extremely selective inhibitors of human immunodeficiency virus type 1 (HIV-1) replication in vitro. These include the tetrahydro-imidazo[4,5,1-jk][1,4]-benzodiazepin-2(1H)-one and -thione (TIBO), 1-(2-hydroxyethoxymethyl)-6-(phenylthio)-thymine (HEPT), dipyridodiazepinone, pyridinone and bis(heteroaryl)piperazine derivatives. The hallmark of these new antiviral compounds is a specific interaction with reverse transcriptase (RT) of HIV-1. They are inactive against HIV-2 and any other viruses tested. Here we describe that, in addition to the HIV-1 strains, two simian immunodeficiency virus (SIV) strains from African green monkeys (SIVagm3 and SIVagmTYO-1) are also sensitive to the TIBO class of compounds. TIBO and HEPT derivatives block the replication of SIVagm in cell culture at micromolar concentrations. Kinetics of inhibition of SIVagm RT by TIBO are competitive with respect to the natural substrate (dGTP). Amino acid alignments and site-directed mutagenesis point to the critical role of amino acid residues Y181 and Y188 in the sensitivity of HIV-1 RT and SIVagm RT to inhibition by the TIBO derivatives. Antiviral efficacy studies with this range of compounds and using sensitive SIV strains are now feasible in monkeys.
最近，几类化合物已被证明是体外人类免疫缺陷病毒1型（HIV-1）复制的极具选择性的抑制剂。这些化合物包括四氢咪唑并[4,5,1-jk][1,4]-苯并二氮杂卓-2(1H)-酮和 -硫酮（TIBO）、1-(2-羟基乙氧基甲基)-6-(苯硫基)-胸腺嘧啶（HEPT）、二吡啶并二氮杂酮、吡啶酮和双（杂芳基）哌嗪衍生物。这些新型抗病毒化合物的标志是与HIV-1的逆转录酶（RT）发生特异性相互作用。它们对HIV-2和任何其他测试病毒均无活性。在此我们描述，除了HIV-1毒株外，来自非洲绿猴的两种猿猴免疫缺陷病毒（SIV）毒株（SIVagm3和SIVagmTYO-1）也对TIBO类化合物敏感。TIBO和HEPT衍生物在微摩尔浓度下可阻断细胞培养中SIVagm的复制。TIBO对SIVagm RT的抑制动力学相对于天然底物（dGTP）是竞争性的。氨基酸序列比对和定点诱变表明，氨基酸残基Y181和Y188在HIV-1 RT和SIVagm RT对TIBO衍生物抑制的敏感性中起关键作用。现在，使用这类化合物并针对敏感SIV毒株进行抗病毒疗效研究在猴子身上是可行的。
