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Mechanisms of protein denaturation and design of new inhibitors of protein aggregation for the pharmacological treatment of Alzheimer and other condensation diseases

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The main goal of this work is an investigation of the mechanisms of progression of different amyloid diseases (e.g. Alzheimer's disease and bovine spongiform encephalopathy). We would like to verify whether misfolded proteins and their interactions with chaperones could play a significant role in the formation of amyloid structures. We speculate that accumulation of different misfolded proteins (as a result of oxidation, chemical modification, and thermal inactivation) could inhibit the chaperone system that promotes aggregation of amyloid proteins. Besides, we are planning to study antidenaturant properties of different natural and synthetic low-molecular-weight compounds in systems containing amyloid proteins, chaperones, and misfolded proteins and to prepare new antidenaturant agents. A great number of pathologies are connected with the formation of the aggregates of specific proteins in cells, such as amyloid plaques (Alzheimer's disease), aggregates of infectious prions (bovine spongiform encephalopathy) and crystallines (cataract).

It was reported that glyceraldehyde-3-phosphate dehydrogenase (GAPDH) can form amyloid fibrils and forms complexes with beta-amyloids. Since the physiological significance of the described processes is little studied, it is of importance to investigate the mechanisms of aggregation of both amyloid and usual proteins so as to understand the connection between these processes.

The first part of this project is devoted to investigation of aggregation of amyloid and usual proteins and the role of chaperones, misfolded proteins, proline-containing peptides, polyelectrolytes, and particularly conjugates of the proteins with polyelectrolytes in this process. We aim at elucidating the role of these interactions in the pathological transformation of normal proteins. Since Alzheimer's disease and bovine spongiform encephalopathy result in the aggregation of the amyloids or infectious prions, one can expect that compounds preventing this aggregation could be effective drugs for these diseases. It is known that natural chaperones prevent aggregation of proteins. Consequently, different types of artificial chaperones that prevent protein aggregation can serve as drugs against the condensation diseases.

The second part of the project is connected with elaborating antidenaturating and antiaggregating drugs based on low molecular-weight compounds, proline-containing peptides, monoclonal antibodies against denatured proteins, polyelectrolytes, and conjugates of monoclonal antibodies with polyelectrolyte complexes.

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University of Rome La Sapienza
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P.le Aldo Moro 5
00185 Rome
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Letzte Aktualisierung: 6 September 2004

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Permalink: https://cordis.europa.eu/project/id/INTAS2003-51-4813/de

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