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Current Medicinal Chemistry


ISSN (Print): 0929-8673
ISSN (Online): 1875-533X

Therapeutic Targets in Extracellular Protein Deposition Diseases

Author(s): A. R. Wyatt, J. J. Yerbury, S. Poon and M. R. Wilson

Volume 16, Issue 22, 2009

Page: [2855 - 2866] Pages: 12

DOI: 10.2174/092986709788803187

Price: $65


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 Alzheimers 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, protein aggregation, protein deposition diseases, extracellular chaperones, receptormediated endocytosis, therapeutic targets

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