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.
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