PROPERTIES OF CONSTRAINED CYCLIC PSEUDOPEPTIDES

含有一个或多个主链修饰的多肽通常 提高了对蛋白质降解的稳定性，并且 不同的构象、电子和溶解性性质。我们 建议继续我们对 模型环状伪肽的构象性质， 评价制备它们的新的合成方法，以及 研究酰胺键的生物后果 在几个小的环状生物活性亲本中的替换，包括 Cyclo(Pro-Phe-Met-Gly-D-Trp-Met)，一种新的CCK 具有选择性中枢受体亲和力的类似物，在小、有效、 生长抑素类似物，后来在其他适当的宿主中。 修饰的环状伪肽代表着潜在的有用 新的基于多肽的候选药物以及 选择性酶抑制剂。但这些化合物也提供了一种 一种新型大环制备的替代方法 立体化学定义的侧链成分。这个 要制备的大环将包含PSi(CH2S)， PSI(CH2NH)和PSI(CSNH)酰胺替代物和侧链 功能将包括酸性和碱性成分。 遵循完整的结构和构象 表征、选择性离子配位的可能性或 定制的催化活性也将被调查。这个 假设有效的酶模拟物可能是最好的 从氨基酸和修饰的氨基酸的组合中 结构将是我们实验方法的中心主题。

Peptides containing one or more backbone modifications often have improved stability toward proteolytic degradation, and diverse conformational, electronic, and solubility properties. We propose to continue our systematic evaluation of the conformational properties of model cyclic pseudopeptides, evaluate new synthetic procedures for their preparation, and investigate the biological consequences of amide bond replacements in several small cyclic bioactive parents, including cyclo (Pro-Phe-Met-Gly-D-Trp-Met), a recently described CCK analog with selective central receptor affinity, in small, potent, somatostatin analogs, and later in other appropriate hosts. Modified cyclic pseudopeptides represent potentially useful species for new peptide-based drug candidates as well as for selective enzyme inhibitors. But these compounds also provide an alternative approach for novel macrocycle preparation with stereochemically defined side chain constituents. The macrocycles to be prepared will incorporate psi(CH2S), psi(CH2NH), and psi(CSNH) amide surrogates, and side chain functionalities will include both acidic and basic constituents. Following complete structural and conformational characterization, the possibility of selective ion coordination or customized catalytic activity will also be investigated. The hypothesis that effective enzyme mimetics may be best fashioned from a combination of amino acid and modified amino acid structures will be a central theme of our experimental approach.