PROPERTIES OF CONSTRAINED CYCLIC PSEUDOPEPTIDES

具有多种酰胺键取代的假肽 (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])被证明具有不同的集合 物理、结构和构象性质的。当明智地 选择正确的替代物，可以提供更多的肽类似物 稳定性，改进的效力，优化的溶解度，口服活动，以及， 有时，增强了选择性，甚至具有拮抗作用。在这 更新我们计划利用一处房产的优势，即 经常对我们检查的许多替代产品造成损害，即增加 灵活性。将制备线性和环状伪肽类似物 和彻底的特色化。具体目标包括：1) 多个酰胺取代的类似物的制备。这些将是 设计为提供更好的氢键，以增加分子内 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)以稳定β转角或螺旋；2)概念 伪肽“诱导契合”将通过与 主干修饰旨在防止酶的分解 构象约束旨在提供优化的结合和 选择性：最初寻找的目标类似物是法尼基转移酶 抑制剂。选择性的预烯基化抑制剂可能会有广泛的 生化和治疗潜力；3)小环精选 生物活性多肽将被用于应用我们的研究结果 环状伪肽的构象研究。例如， 新近分离的内皮素拮抗剂Cyclo[D-Val-L-Leu-D-Trp-D-Glu-L- ALA]将被用作各种氨基酸的宿主和替代品 旨在稳定拟议的贝塔和伽马转向的替代方案。这些 化合物将在体外和体内进行潜在的测试 抗高血压活性。最后，我们建议扩大我们的合成 纳入更多三功能和四功能PSI实例的途径[CH(2)S] 伪二肽。这些将被用来制备新型大环化合物，如 以及线性Arg-Arg替代物。他们对特定对象的行为 蛋白水解酶将用反相色谱进行测定。

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.