DESIGN AND SYNTHESIS OF NOVEL PSEUDOPEPTIDES

这项研究计划的总体目标是发明和发展 新的多肽模拟物作为结构和结构的等位取代物 生物活性寡肽的功能基质。为此， 我们将采用合成有机化学、分子 酶抑制剂复合体的建模、结构研究(核磁共振和X-射线)， 并构建活动关系。我们的努力将集中在 新型替代物的设计，如1，2，3-三取代环丙烷 增加了肽骨架的结构刚性，同时限制了 氨基酸侧链可利用的构象空间。一个有价值的 用1，2，3-三取代环丙烷取代二肽的特点 子单元是此代理将主干链的几何形状锁定在 一条测试链，同时强制执行特定的方向 氨基酸侧链。这一模拟应该会增强 通过减少结合时发生的熵损失而产生的假肽。 1，2，3-三取代环丙烷等的一般适用性 新的多肽模拟物将通过将它们合并为亚单位来建立 在针对天冬氨酸蛋白酶的抑制配体中，肾素和 HIV-1多蛋白水解酶，尽管我们预计在 这些努力可能会扩展到多肽模拟的其他领域。卵裂 肾素对血管紧张素原的作用是酶的速率决定步骤 释放强大的升压八肽血管紧张素II.HIV-1的级联反应 POL-蛋白酶对病毒复制和成熟HIV-2的形成至关重要。 1感染细胞中的颗粒。1，2，3-三取代环丙烷 可以有效地利用作为异构型二肽替代物 通过我们实验室的初步实验令人信服地建立起来 随着具有这样的肾素抑制剂的设计和制备 用亚纳米分子IC50取代P3位点。S：未来 研究将需要合成含有以下成分的假肽 1，2，3-三取代环丙烷作为二肽在P1，P， 和潜在肾素抑制剂的P3位点，以及跨越P2- HIV-1多聚蛋白酶潜在抑制物的P2‘一致序列。 在这些调查过程中，调查的一般方法 发明1，2，3-三取代环丙烷的不对称合成 并得到了发展。潜在肾素和HIV蛋白水解酶的生物学评价 抑制剂将在雅培实验室进行。我们预料到 治疗高血压和艾滋病的新药候选药物将 从这些调查中浮现出来。我们还预计，这些研究 将提高我们对结构、构象和 作为受体-配体结合基础的动态特征以及由此产生的 多肽配体的生物学特性。

The overall goal of this research program is the invention and development of novel peptide mimics as isosteric replacements for the structural and functional matrix of biologically active oligopeptides. Toward this end, we will employ a combination of synthetic organic chemistry, molecular modeling, structural studies (NMR and X-ray) of enzyme-inhibitor complexes, and structure activity relationships. Our efforts will be focused upon the design of novel surrogates such as 1,2,3-trisubstituted cyclopropanes that add structural rigidity to the peptide backbone while restricting the conformational space available to the amino acid side chains. A valuable feature of substituting a 1,2,3-trisubstituted cyclopropane for a dipeptide subunit is that this surrogate locks the geometry of the backbone chain in a beta-strand while simultaneously enforcing specific orientation of the amino acid side chain. This mimic should enhance binding of the pseudopeptide by reducing the loss of entropy that occurs upon binding. The general applicability of 1,2,3-trisubstituted cyclopropanes and other new peptide mimics will be established by their incorporation as subunits in inhibitory ligands directed against the aspartate proteases renin and HIV-1 pol-protease, although we anticipate that discoveries made during these efforts may be extended to other areas of peptide mimetics. Cleavage of angiotensinogen by renin is the rate determining step in an enzymic cascade that releases the potent pressor octapeptide angiotensin II. HIV-1 pol-protease is critical for viral replication and formation of mature HIV- 1 particles from infected cells. That 1,2,3-trisubstituted cyclopropanes may be effectively employed as isosteric dipeptide replacements has been convincingly established by preliminary experiments in our laboratories with the design and preparation of renin inhibitors bearing such replacements at the P3 site with subnanomolar IC50's. Future investigations will entail syntheses of pseudopeptides that incorporate 1,2,3-trisubstituted cyclopropanes as dipeptide surrogates at the P1, P2, and P3 sites of potential renin inhibitors and at sites spanning the P2 - P2' consensus sequence of potential inhibitors of HIV-1 pol-protease. During the course of these investigations, general methods for the asymmetric synthesis of 1,2,3-trisubstituted cyclopropanes will be invented and developed. Biological evaluation of potential renin and HIV-protease inhibitors will be performed at Abbott Laboratories. We anticipate that novel drug candidates for the treatment of hypertension and AIDS will emerge from these investigations. We also anticipate that these studies will improve our understanding of the structural, conformational, and dynamic features that underlie receptor-ligand binding and consequent biological properties of peptide ligands.