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      Novel Pharmacological Strategies in Amyloidosis

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          Amyloidosis is a disorder of protein folding in which normally soluble plasma proteins are deposited as insoluble fibrils that disrupt tissue structure. Over 20 unrelated proteins form amyloid in vivo, with fibrils sharing a cross-β-sheet structure composed of non-covalently associated protein or peptide subunits. Glycosaminoglycans and serum amyloid P component are universal non-fibrillar constituents of amyloid, contributing to fibrillogenesis and the stability of amyloid deposits. Amyloidosis may be acquired or hereditary and local or systemic, and is classified according to the precursor protein. Current treatment consists of support or replacement of impaired organ function and measures to reduce the production of amyloidogenic precursor proteins. Potential novel therapeutic strategies include stabilisation of the native fold of precursor proteins, reversion of misfolded proteins to their native state, inhibition of fibril propagation and enhancement of amyloid clearance either through immunotherapy or by reducing the stability of deposits through depletion of serum amyloid P component.

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          Most cited references 5

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          Instability, unfolding and aggregation of human lysozyme variants underlying amyloid fibrillogenesis.

          Tissue deposition of soluble proteins as amyloid fibrils underlies a range of fatal diseases. The two naturally occurring human lysozyme variants are both amyloidogenic, and are shown here to be unstable. They aggregate to form amyloid fibrils with transformation of the mainly helical native fold, observed in crystal structures, to the amyloid fibril cross-beta fold. Biophysical studies suggest that partly folded intermediates are involved in fibrillogenesis, and this may be relevant to amyloidosis generally.
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            Conformational Abs recognizing a generic amyloid fibril epitope.

            Disease-related amyloid fibrils appear to share a common, but poorly understood, structure. We describe here the generation and preliminary characterization of two conformation-specific mAbs, WO1 and WO2, that bind to the amyloid fibril state of the Alzheimer's peptide A beta(1-40) but not to its soluble, monomeric state. Surprisingly, these Abs also bind to other disease-related amyloid fibrils and amyloid-like aggregates derived from other proteins of unrelated sequence, such as transthyretin, islet amyloid polypeptide, beta(2)-microglobulin, and polyglutamine. At the same time, WO1 and WO2 do not bind to the native protein precursors of these amyloids, nor do they bind to other kinds of protein aggregates. This new class of Abs associated with a fundamental amyloid-folding motif appear to recognize a common conformational epitope with little apparent dependence on amino acid side chain information. These Abs should contribute to the understanding of amyloid structure, assembly, and toxicity and also may benefit the development of diagnostic and therapeutic agents for amyloid diseases.
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              Targeted pharmacological depletion of serum amyloid P component for treatment of human amyloidosis.

              The normal plasma protein serum amyloid P component (SAP) binds to fibrils in all types of amyloid deposits, and contributes to the pathogenesis of amyloidosis. In order to intervene in this process we have developed a drug, R-1-[6-[R-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]pyrrolidine-2-carboxylic acid, that is a competitive inhibitor of SAP binding to amyloid fibrils. This palindromic compound also crosslinks and dimerizes SAP molecules, leading to their very rapid clearance by the liver, and thus produces a marked depletion of circulating human SAP. This mechanism of drug action potently removes SAP from human amyloid deposits in the tissues and may provide a new therapeutic approach to both systemic amyloidosis and diseases associated with local amyloid, including Alzheimer's disease and type 2 diabetes.

                Author and article information

                Nephron Clin Pract
                Nephron Clinical Practice
                S. Karger AG
                August 2003
                17 November 2004
                : 94
                : 4
                : c85-c88
                National Amyloidosis Centre, Department of Medicine, Royal Free and University College Medical School, Royal Free Hospital, London, UK
                72490 Nephron Clin Pract 2003;94:c85–c88
                © 2003 S. Karger AG, Basel

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                Figures: 1, Tables: 1, References: 17, Pages: 1
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