Therapeutic Targets in Extracellular Protein Deposition Diseases

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Abstract:

Many litres of fluids are found outside cells in the human body. These fluids are rich in dissolved proteins that each have a characteristic three dimensional shape, necessary for normal function, which has been attained by the correct folding of their polypeptide chain(s). The structure of these extracellular proteins can be damaged by a variety of environmental stresses (e.g. heat and oxidation) leading to their partial unfolding and aggregation. This in turn can produce toxic soluble aggregates and/or large insoluble protein deposits, either of which can disrupt normal body function (e.g. in Alzheimer's disease and the systemic amyloidoses). A small family of abundant human blood proteins with the ability to inhibit the aggregation and deposition of stressed (partially unfolded) proteins has been discovered. These extracellular chaperones (ECs) form stable, soluble complexes with stressed proteins. It has been proposed that once bound to stressed proteins, ECs guide them to specific cell surface receptors that direct the “cargo” into lysosomes for degradation. Thus ECs and their receptors may be critical parts of a quality control system to protect the body against the deleterious effects of inappropriately aggregating extracellular proteins. This review focuses on the role of extracellular protein aggregation and deposition in disease, what little is known about mechanisms that act to control these processes, and, lastly, potential new targets for drug development. Newly identified potential drug targets include direct inhibition of protein aggregation, and manipulation of the expression levels of ECs and their receptors.

Keywords: Extracellular protein unfolding; extracellular chaperones; protein aggregation; protein deposition diseases; receptormediated endocytosis; therapeutic targets

Document Type: Research Article

DOI: http://dx.doi.org/10.2174/092986709788803187

Affiliations: School of Biological Sciences, University of Wollongong. Northfields Avenue, Wollongong. NSW. 2522. Australia.

Publication date: August 1, 2009

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  • Current Medicinal Chemistry covers all the latest and outstanding developments in medicinal chemistry and rational drug design. Each issue contains a series of timely in-depth reviews written by leaders in the field covering a range of the current topics in medicinal chemistry. Current Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments.
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