PROPERTIES OF CONSTRAINED CYCLIC PSEUDOPEPTIDES

具有多种酰胺键置换的假肽 （psi[CH（2）S]，psi[CH（2）SO]，psi[CH（2）NH]，psi[CH（2）NH（2）]， psi[CH（2）SO（2）]和psi[CSNH]）已被证明具有不同的集合 物理的，结构的，和构象的特性。 当明智地 选择正确的替代物可以提供肽类似物， 稳定性、改进的效力、优化的溶解度、口服活性，以及， 有时，增强的选择性或甚至拮抗剂性质。 在这 更新，我们建议利用一个属性的优势， 这往往损害了我们许多检查的替代品，即，增加 灵活性. 将制备线性和环状假肽类似物 并被彻底描述。 具体目标包括：1） 制备具有多个酰胺置换的类似物。 这些将是 经改造以提供改进的H键合， 稳定化，例如，使用改进的给体（CH（2）NH（2））和改进的 受体（CH（2）SO）稳定β-转角或螺旋; 2）概念 假肽“诱导契合”将通过以下结合来探索： 主链修饰旨在防止酶分解沿着 具有旨在提供最佳结合的构象约束， 选择性：最初寻找的靶类似物为法尼基转移酶 抑制剂的 异戊二烯化的选择性抑制剂可能具有广泛的 生物化学和治疗潜力; 3）小环的选定实例 生物活性肽将用于应用我们的研究结果， 环状假肽的构象研究。 比如说 最近分离的内皮素拮抗剂环[D-Val-L-Leu-D-Trp-D-Glu-L- Ala]将用作各种酰胺酸的宿主和替代物 旨在稳定拟议的β和γ转弯的替代品。 这些 将在体外和体内测定化合物的潜在活性， 抗高血压活性 最后，我们建议扩大我们的合成 路线以包括更多的三官能和四官能的psi[CH（2）S] 假二肽 这些将用于制备新型大环化合物，如 以及线性Arg-Arg替代物。 他们对特定的 蛋白水解酶将使用反相色谱法测定。

Pseudopeptides with a wide variety of amide bond replacements (psi[CH(2)S], psi[CH(2)SO], psi[CH(2)NH], psi[CH(2)NH(2)], psi[CH(2)SO(2)], and psi[CSNH]) have been shown to possess a diverse set of physical, structural, and conformational properties. When judiciously chosen, the correct surrogate can provide peptide analogs with increased stability , improved potency, optimized solubility, oral activity, and, sometimes, enhanced selectivity or even antagonist properties. In this renewal we propose to exploit the advantages of one property that is often a detriment of many of our examined replacements, namely, increased flexibility. Both linear and cyclic pseudopeptide analogs will prepared and thoroughly characterized. Among specific objectives are: 1) the preparation of analogs with multiple amide replacements. These will be engineered to provide improved H-bonding for increased intramolecular stabilization, e.g., using an improved donor (CH(2)NH(2)) and an improved acceptor (CH(2)SO) to stabilize a beta-turn or helix; 2) the concept of pseudopeptide "induced fit" will be explored by the conjunction of backbone modifications designed to protect against enzyme breakdown along with conformational constraints intended to provide optimized binding and selectivity: target analogs are initially sought as farnesyl transferase inhibitors. Selective inhibitors of prenylation could have widespread biochemical and therapeutic potential; 3) selected examples of small ring biologically active peptides will be used to apply the findings from our conformational studies on cyclic pseudopeptides. For example, the recently isolated endothelin antagonist cyclo[D-Val-L-Leu-D-Trp-D-Glu-L- Ala] will be used as a host for a variety of amide acid and surrogate replacements designed to stabilize proposed beta and gamma turns. These compounds will be assayed both in vitro and in vivo for potential antihypertensive activities. Finally, we propose to expand our synthetic routes to include more examples of tri- and tetrafunctional psi[CH(2)S] pseudodipeptides. These will be used to prepare novel macrocyles, as well as linear Arg-Arg surrogates. Their behavior toward specific proteolytic enzymes will be assayed using reversed phase chromatography.