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Peptidic substrates and inhibitors for proteolytic enzymes


The project aims to tackle the study of proteolytic enzymes involved in physiological and physiopathological processes developing substrates and specific inhibitors. The kallikreins, renin, tonin, enzyme converter of angiotensin-I have been studied in our Laboratory for several years and will be prominent in the project. Peptidases of the central nervous system, proenzyme processing enzymes, parasite and snake venom proteases and the cathepsins, will be studied in collaboration. The peptides will be synthesized mostly by classic techniques, in solution, since they will receive the addition of chromophore, fluorescent and fluorescence off-switching radicals. The syntheses of inhibitors will basically follow the same methodology, requiring, nevertheless, a greater range of organic reactions, since we will have to prepare diazo-methylcetones, chlorine and fluoro- methylcetones, aminoacids and amide modified bonds. The kinetic studies of hydrolysis and enzymatic inhibition will be carried out by colorimetric, fluorometric or by HPLC techniques. The enzymes will be obtained from natural sources or by cloning, when we can have access to up-to-the-minute modifications, through collaboration with Dr. Julie Chao of the University of South Carolina, USA. We intend to establish in our Laboratorys the techniques for the preparation of glycopeptides and to study them with inhibitors or substrates of the proteolytic enzymes. The chemistry of the processes of synthesis of glycoproteins is recent and is under development at international level. Little is known of the effect of sugars on the proteolysis of glycosilate substrates. The potential of the work is enormous in this area and totally new in our milieu. It should, however, require investment in equipment, in the development and adaptation of chemical procedures and in the training of personnel. The project presented has by way of support for its completion a complex in Laboratorys and a body of personnel that have been dedicating themselves in the Paulista School of Medicine, to the synthesis and Biology of peptides for at least two generations. (AU)

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