DESIGN AND SYNTHESIS OF NOVEL PSEUDOPEPTIDES

这项研究计划的总体目标是发明和发展 新型肽模拟物作为结构和功能的电子等排替代物， 生物活性寡肽的功能基质。 为此， 我们将采用有机合成化学，分子， 建模，酶抑制剂复合物的结构研究（NMR和X射线）， 和结构活动关系。 我们的努力将集中在 设计新的替代物如1，2，3-三取代的环丙烷， 增加肽骨架的结构刚性，同时限制 氨基酸侧链的构象空间。 一个宝贵 用1，2，3-三取代环丙烷取代二肽的特征 亚基的一个重要特征是，该替代物将主链的几何结构锁定在 β-链，同时加强特定的方向， 氨基酸侧链。 这种模拟物应该增强与 通过减少结合时发生的熵损失来合成假肽。 1，2，3-三取代环丙烷和其他环丙烷的一般适用性 新的肽模拟物将通过它们作为亚基掺入而建立 在针对天冬氨酸蛋白酶凝乳酶和 HIV-1聚合蛋白酶，尽管我们预计， 这些努力可以扩展到肽模拟物的其它领域。 裂解 血管紧张素原的酶促反应是血管紧张素原酶促反应的速率决定步骤。 释放强效升压八肽血管紧张素II的级联反应。 HIV-1 pol-protease对病毒复制和成熟HIV的形成至关重要， 1个来自感染细胞的颗粒。 1，2，3-三取代环丙烷 可以有效地使用，因为电子等排二肽替代物已经 在我们实验室的初步实验中令人信服地建立了 设计和制备具有这种结构的肾素抑制剂 在P3位点的置换具有亚纳摩尔IC 50。 未来 研究将需要合成假肽， 在P1，P2， 和潜在的肾素抑制剂的P3位点，以及跨越P2 - HIV-1 pol-蛋白酶潜在抑制剂的P2'共有序列。 在这些调查过程中， 1，2，3-三取代环丙烷的不对称合成将被发明 和发展。 潜在的肾素和HIV蛋白酶的生物学评价 将在Abbott Laboratories进行抑制剂试验。 我们预计 用于治疗高血压和艾滋病的新型候选药物将 从这些调查中。 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， 肽配体的生物学性质。

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.