KININ SYSTEM ANTAGONISTS

这个项目的目标是开发改进的 具有生物活性的九肽缓激肽及其相关激肽 Kallidin(Lys-BK)和Met-Lys-BK.这些多肽是血管紧张素转换酶的中介。 激肽释放酶-激肽系统的功能，这对调节很重要 血压，血液凝固，分泌物，免疫反应， 炎症、疼痛、肠道运动、生殖、肺功能 和中枢神经系统的功能。激动素似乎参与了 休克、浮肿、关节炎、哮喘、鼻炎的病理以及 毒素和毒液的行为。 我们已经开发了BK的特定的、强有力的竞争对手，方法是 通过对多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7-脯氨酸被 D-苯丙氨酸。进一步的变化赋予了效力、器官特异性和 对酶的抗性。我们将合成新的抑制剂类似物来 寻找更有效和特异的拮抗剂用于生理学和 病理学。利用自动固相多肽合成多肽 合成，并将在这里的分离的平滑肌(大鼠子宫， 豚鼠回肠)和大鼠血压，并将在广泛的 协作研究中的各种系统。 将使用计算机辅助分子图形来了解 激动剂和拮抗剂多肽的构象及其相互作用 通过膜受体。能量最小化计算将预测 原子在空间中最可能的排列方式。 治疗激动素相关疾病的新药最终应该会问世 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.