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Synthetic and structural studies of peptide and polymers: from the improvement of the synthesis methodology and the search for peptide derivatives for biotechnological applications


Five research sub-topics make up this project based heavily on improvements and technological innovations in the complex method of chemical synthesis of peptides made in polymers. This method, known as solid phase synthesis (SPFS), winner of the Nobel Prize in Chemistry in 1984, has been investigated by us at different points in its experimental strategy, allowing us for decades to propose alternatives that have made possible not only the progressive increase in yield of the production of bioactive peptides but also the development of novel polymers and amino acid derivatives with great utility for application in this methodology. More than three dozen articles, specifically, of these efforts have already been published, demonstrating the feasibility, even in our country, to carry out research in the area of complex technology, to achieve synthesis yields that meet the needs even for the level of industrial application. What is intended in this project is the continuation of these efforts. As a typical example of these goals, we have the case of semi-industrial scale production based on the use of an experimental protocol developed by us for a peptide hormone (desmopressin acetate), which after being transformed into a final formulation (nasal solution) as a marketable drug, has been distributed through SUS to patients with Diabetes insipidus. This manufacturing stage and its distribution to the population have been made by the Foundation for Popular Medicine (FURP), the largest official drug producer in the country, linked to the Health Department of the State of São Paulo, in partnership with our University (UNIFESP). This activity of providing services to the community under my coordination began about 15 years ago and will now have to be reassessed both by contractual issues among the institutions involved and by the urgent need for innovative modifications in the protocol of large scale chemical synthesis of peptides (details later). This is due to the fact that we have recently received an official request from the FURP´s Superintendency to continue as a collaborator, as we have done for all this time, to supply this peptide and even others of interest to this São Paulo state Foundation. In addition to these efforts of this block of strong biotechnological application in the chemistry area, we intend to advance also in the synthesis and studies of peptides of physiological interest but preferably containing unnatural organic compounds in their sequences for the purpose of structural, pharmacological and also enzymatic studies, involving in the latter case the angiotensin converting enzyme and renin. The peptides to be modified will belong to the renin-angiotensin (RAS) and kallikrein-kinin (SCC) systems. In addition, we will continue to improve the chemical synthesis yield of peptides containing "difficult" sequences, such as transmembrane receptor fragments of GPCR-type or of others also highly aggregating segments, such as those involved in neurodegenerative diseases. In complement, peptide derivatives containing two amino acid-type spin probes introduced by our group for use in the chemistry of peptides and polymers (Toac and Poac) will be obtained, for different applications, being the last spin label in the elucidation phase of the most efficient large chiral chromatographic purification method of its trans enantiomers (3S4S and 3R4R) for further peptide or polymer labeling. Recent results of some of these sub-topics already presented results with great practical potentiality. In conclusion, we believe that as a whole, this project is clearly characterized by having a reasonable diversification of objectives and all, with outstanding potential in the field of biotechnological application. (AU)

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