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Interpretation of the formation of amyloid fibrils by peptide sequences: relevance to Alzheimer's Disease and type 2 Diabetes

Grant number: 14/01452-5
Support type:Scholarships in Brazil - Scientific Initiation
Effective date (Start): March 01, 2014
Effective date (End): February 28, 2015
Field of knowledge:Biological Sciences - Biochemistry - Chemistry of Macromolecules
Principal Investigator:Luciana Malavolta Quaglio
Grantee:Ricardo Lobato Chinarelli
Home Institution: Faculdade de Ciências Médicas da Santa Casa de São Paulo (FCMSCSP). Fundação Arnaldo Vieira de Carvalho. São Paulo , SP, Brazil
Associated research grant:10/20197-5 - Development of biomarkers for amyloid plaques: relevance for the study of Alzheimer's Disease, AP.JP

Abstract

Although extremely important, the problem of insolubility of peptides and proteins is still far from being fully understood. A high tendency to unite into insoluble aggregates is a serious limitation to the production and use of many peptides and proteins on a broad spectrum of biological and pharmaceutical applications. In physiological terms, the best known cases of pathologies related with insolubilization of peptide segments in the body are called amyloidosis, that are characterized by amyloid fibrils deposit in the body and are associated with dozens of human degenerative diseases including Alzheimer's, Diabetes Type II , Prion , Huntington's and Parkinson's disease as well. In the aggregation process, we can observe an enormous complexity of association / molecular dissociation, dependent on numerous factors. Besides the characteristics of the peptide sequence itself and its conformation, influences of pH, chaotropic agents and especially the combination of electrophilic, nucleophilic properties and the ability to induce electrostatic and van der Waals interactions of the solvent and the solute also were detected, and could lead at the end to a strong tendency to insolubilization of a particular peptide sequence. Thus, this Scientific Initiation project will expand and diversify the investigation of this complex process of molecular associations, keeping the focus certainly in the class of sequences involved in Alzheimer's disease and Type II Diabetes. In other words, our focus will be primarily dedicated to a better understanding of the insolubility of peptide segments in solution mechanism, evaluating the factors that can inhibit this process clearly of physicochemical nature. This project seems extremely relevant in the academic context, since it involves a line of little explored research area involving the synthesis and characterization of peptides with physiological relevance as a proposed study of amyloidogenic diseases, in particular Alzheimer's and Diabetes mellitus type II. The implications of the results are broad. In the field of chemistry and physics will be investigated the aggregation mechanism of peptide segments in solution, evaluating the factors that can inhibit this process clearly of physicochemical nature. In medicine, early detection and understanding of the formation of fibrils in this case related to Alzheimer's disease and diabetes mellitus type II is expected to bring major advances in the treatment of this disease with clinical relevance that affects millions of people worldwide. (AU)