Hydroxyethylamine analogues of the p17/p24 substrate cleavage site are tight-binding inhibitors of HIV protease.
Hydroxyethylamine analogues of the p17/p24 substrate cleavage site are tight-binding inhibitors of HIV protease.
复制标题
p17/p24 底物裂解位点的羟乙胺类似物是 HIV 蛋白酶的紧密结合抑制剂。
DOI：
10.1021/jm00167a003
复制
发表时间：
1990
影响因子：
7.3
通讯作者：
Kent,SB
中科院分区：
文献类型：
--
作者：
Rich,DH;Green,J;Toth,MV;Marshall,GR;Kent,SB
HIV-1蛋白酶是逆转录病毒编码的蛋白水解酶，它切割前体gag和pol蛋白中的特异性酰胺键，形成产生感染性病毒颗粒所需的成熟蛋白，这是HIV复制的关键步骤。1通过定点突变技术取代蛋白质前体中的催化活性残基，导致非感染性病毒体的形成，2因此，HIV蛋白酶被认为是开发治疗获得性免疫缺陷综合征（AIDS）及相关疾病的药物的潜在靶点。几种X-射线晶体结构已经确定，成熟的HIV蛋白酶是由两个相同的99个氨基酸肽形成的天冬氨酸蛋白酶，每个亚基贡献一个Asp-Thr-Gly单位。3 - 6如此形成的活性位点与在其它充分表征的天冬氨酸蛋白酶中发现的活性位点非常相似7 8 - 9 1011，并证实了基于序列同源性预测的HIV蛋白酶的某些性质。10，11成熟的HIV蛋白酶是天冬氨酸蛋白酶的发现向我们和其他人12 ®"®建议，用过渡态类似物替换底物中的Pj-P/切割点的一般设计策略可用于设计HIV蛋白酶的紧密结合抑制剂，以同样的方式，该方法用于制备其他天冬氨酸蛋白酶的抑制剂，例如胃蛋白酶、青霉菌胃蛋白酶、肾素、组织蛋白酶D。13我们在此报道了羟乙胺（HEA）二肽基电子等排体1和2的合成，它们被设计成模拟水解Tyr-Pro的四面体中间体（3），Tyr-Pro是HIV蛋白酶切割的部分底物序列之一（图1）。羟乙基胺1和2在相关肽中的掺入
A key step in the replication of the human immunodeficiency virus (HIV) occurs when HIV-1 protease, the proteolytic enzyme encoded by the retrovirus, cleaves specific amide bonds in precursor gag and pol proteins to form the mature proteins needed for production of infec-tious viral particles. 1 Replacement of the catalytically active residues in protein precursors by site-directed mu-tagenesis techniques leads tothe formation of noninfective virions, 2 and for this reason HIV protease is regarded as a potential target for developingagents for the treatment of acquired immunodeficiency syndrome (AIDS) and re-lated diseases. Several X-ray crystalstructures have es-tablished that the mature HIV protease is an aspartic proteinase that is formed from two identical 99 amino acid peptides, each subunit contributing one Asp-Thr-Gly unit. 3" 6 The active site so formed closelyresembles the active sites found in other well-characterized aspartic proteinases7 8" 9 1011and confirms some of the properties of HIV protease that were predicted on the basis of sequence homology. 10, 11 The discovery that mature HIV protease is an aspartic proteinase suggested to us and others12®"® that the general design strategyof replacing the Pj-P/cleavage point in substrates with transition-state analogues could be used to design tight-binding inhibitors of HIV protease, in the same way this approach was used to prepare inhibitors of other aspartic proteinases, eg pepsin, penicillopepsin, renin, cathepsin D. 13 We report herein the synthesis of hydroxyethylamine (HEA) dipeptidyl isosteres 1 and 2 that were designed to mimic the tetrahedral intermediate (3) for hydrolysis of Tyr-Pro, one of the partial substrate sequences cleavedby HIV protease (Figure 1). Incorporation of hydroxyethylamines 1 and 2 in peptides related