KININ SYSTEM ANTAGONISTS

该项目的目标是开发改进的拮抗剂 具有生物活性的九肽缓激肽 (BK) 和相关激肽 激肽 (Lys-BK) 和 Met-Lys-BK。 这些肽是 激肽释放酶-激肽系统的功能，这对于调节很重要 血压、凝血、分泌、免疫反应、 炎症、疼痛、肠道蠕动、生殖、肺功能 和中枢神经系统功能。 激肽似乎参与 休克、水肿、关节炎、哮喘和鼻炎的病理学以及 毒素和毒液的作用。 我们通过以下方式开发了 BK 的特异性、强效竞争性拮抗剂： 肽序列中某些氨基酸的特定替换 非天然氨基酸；关键的变化是将 7-脯氨酸替换为 D-苯丙氨酸。 进一步的变化赋予效力、器官特异性和 酶抗性。 我们将合成新的抑制剂类似物 寻找更有效和特异性的拮抗剂用于生理学研究和 病理学。 全自动固相肽合成 合成并将在分离的平滑肌（大鼠子宫， 豚鼠回肠）和大鼠血压，并将在广泛的范围内进行测试 协作研究中的各种系统。 计算机辅助分子图形将用于了解 激动剂和拮抗剂肽的构象及其相互作用 与膜受体。 能量最小化计算将预测 原子在空间中最可能的排列。 治疗激肽相关疾病的新药最终应该会出现 从这些研究中。

The goal of this project is to develop improved antagonists of the biologically active nonapeptide bradykinin (BK) and the related kinins kallidin (Lys-BK) and Met-Lys-BK. These peptides are the mediators of the functions of the kallikrein-kinin system, which is important for regulation of blood pressure, blood clotting, secretion, the immune response, inflammation, pain, intestinal motility, reproduction, pulmonary function and central nervous system function. The kinins appear to be involved in the pathology of shock, edema, arthritis, asthma and rhinitis as well as the actions of toxins and venoms. We have developed specific, potent competitive antagonists of BK by making specific replacements of certain amino acids in the peptide sequence by unnatural amino acids; the critical change is replacement of 7-proline by D-phenylalanine. Further changes confer potency, organ specificity and enzyme resistance. We will synthesize new analogs of the inhibitors to find more potent and specific antagonists for studies of physiology and pathology. Peptides will be synthesized by automatic solid phase peptide synthesis and will be assayed here on isolated smooth muscles (rat uterus, guinea pig ileum) and in rat blood pressure and will be tested in a wide variety of systems in collaborative studies. Computer-assisted molecular graphics will be used to gain understanding of conformations of agonist and antagonist peptides and their interactions with membrane receptors. Energy minimization calculations will predict most probable arrangements of the atoms in space. New drugs for treatment of kinin-related pathologies should eventually come from these studies.