PROPERTIES OF CONSTRAINED CYCLIC PSEUDOPEPTIDES

受限环状伪肽的性质

• 批准号: 3283046
• 负责人: ARNO F SPATOLA
• 金额: $ 12.75万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 1985
• 资助国家: 美国
• 起止时间: 1985-04-01 至 1993-03-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3283046
• 关键词: amides; chemical models; cholecystokinin; conformation; cyclic peptides; electrochemistry; enzyme inhibitors; peptide structure; proteolysis; solubility; somatostatin; stereochemistry

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.

含有一个或多个骨架修饰的肽通常 具有改善的对蛋白水解降解的稳定性，和 不同的构象、电子和溶解度性质。 我们 我们建议继续系统地评估 模型环状假肽的构象性质， 评价新的合成方法， 研究酰胺键的生物学后果 在几个小的环状生物活性的父母，包括 cyclo（Pro-Phe-Met-Gly-D-Trp-Met），最近描述的CCK 具有选择性中心受体亲和力的类似物，以小，有效， 生长抑素类似物，以及后来在其他适当的宿主中。 修饰的环状假肽代表了潜在的有用的 用于新的基于肽的候选药物以及用于 选择性酶抑制剂。 但这些化合物也提供了 制备新大环化合物的替代方法， 立体化学定义的侧链成分。 的 要制备的大环化合物将掺入PSi（CH 2S）， psi（CH 2NH）和psi（CSNH）酰胺替代物，以及侧链 官能团将包括酸性和碱性成分。 在完成结构和构象 表征，选择性离子配位的可能性或 还将研究定制的催化活性。 的 假设有效的酶模拟物可能是最好的塑造 从氨基酸和修饰的氨基酸的组合 结构将是我们实验方法的中心主题。