INHIBITION OF HUMAN IMMUNODEFICIENCY VIRUS-1 PROTEASE INVITRO - RATIONAL DESIGN OF SUBSTRATE-ANALOG INHIBITORS
INHIBITION OF HUMAN IMMUNODEFICIENCY VIRUS-1 PROTEASE INVITRO - RATIONAL DESIGN OF SUBSTRATE-ANALOG INHIBITORS
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DOI：
10.1073/pnas.86.24.9752
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发表时间：
1989-12-01
影响因子：
11.1
通讯作者：
MEEK, TD
中科院分区：
文献类型：
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作者：
DREYER, GB;METCALF, BW;MEEK, TD
设计、合成了人类免疫缺陷病毒1 （HIV-1）蛋白酶抑制剂，并对其进行了动力学表征。HIV-1蛋白酶的七肽底物类似物，其序列与天然底物Pr55gag中的p17-p24切割位点相似，其中可剪切的二肽键被六类稳定的天冬氨酸蛋白水解过渡态或中间体的模拟键所取代。这些模拟物包括他汀的类似物、羟乙烯异构体、两类膦酸、还原酰胺异构体和α、α -二氟酮。得到的肽类似物是纯化的重组HIV-1蛋白酶的线性竞争性抑制剂，抑制常数在18 nM到40 .mu之间。M取决于抑制剂的类型。截断的抑制剂，六肽的类似物，保留了充分的抑制效力。在无细胞实验中，最有效的抑制剂，含有羟基乙烯异构体，有效地阻断了HIV-1蛋白酶对重组Pr55gag的蛋白水解过程。
Inhibitors of the protease from human immunodeficiency virus 1 (HIV-1) were designed, synthesized, and kinetically characterized. Analogues of a heptapeptide substrate of HIV-1 protease with sequence similar to the p17-p24 cleavage site in the natural substrate, Pr55gag, were synthesized in which the scissile dipeptide bond was replaced with bonds from six categories of stable mimics of an aspartic proteolysis transition state or intermediate. These mimics included an analogue of statine, hydroxyethylene isosteres, two categories of phosphinic acids, a reduced amide isostere, and an .alpha.,.alpha.-difluoroketone. The resulting peptide analogues were linear competitive inhibitors of purified recombinant HIV-1 protease with inhibition constants ranging from 18 nM to 40 .mu.M depending on the type of inhibitor. A truncated inhibitor, an analogue of a hexapeptide, retained full inhibitory potency. The most potent inhibitors, containing the hydroxyethylene isostere, effectively blocked the proteolytic processing of a recombinant form of Pr55gag by HIV-1 protease in a cell-free assay.