Design, synthesis, kinetic analysis, molecular modeling, and pharmacological evaluation of novel inhibitors of peptide amidation
Foster, Michael Scott
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Novel, rationally-designed acrylate analogs of various known dipeptide substrates were found to be mechanism-based inactivators of the enzyme peptidylglycine alpha-amidating monooxygenase (PAM, EC 188.8.131.52). This enzyme is responsible for the rate-limiting and final bioactivation step, a C-terminal amidation of glycine-extended peptides, of a variety of peptide hormones including the potent pro-inflammatory compound Substance P. Protein-ligand docking studies, in tandem with in vitro kinetic analysis of these inactivators, indicated that the rational design of this class of compounds was successful in creating potent competitive inactivators of this enzyme. Pharmacological evaluation, via both acute and chronic models of inflammation in Sprague-Dawley rats, of these compounds indicates that they are highly potent anti-inflammatory agents which ameliorate both acute carrageenan-induced edema and the deleterious effects of chronic adjuvant-induced polyarthritis. Furthermore, these compounds were also able to induce a return toward a more normal phenotype in cancerous WB-Ras epithelial cells, via the interruption of the growth factor-stimulated pathway precipitated by Substance P. Finally, our modeling studies provide a structural basis for both the reaction and subsite stereospecificity of PAM toward its substrates, competitive inhibitors, and mechanism-based inactivators.