Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amyloidosis / blood
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Amyloidosis / drug therapy*
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Amyloidosis / metabolism*
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Animals
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Calcium / metabolism
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Carboxylic Acids / chemistry
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Carboxylic Acids / metabolism
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Carboxylic Acids / pharmacology
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Carboxylic Acids / therapeutic use
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Cross-Linking Reagents / chemistry
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Cross-Linking Reagents / metabolism
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Cross-Linking Reagents / pharmacology
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Cross-Linking Reagents / therapeutic use
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Crystallography, X-Ray
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Dimerization
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Humans
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Inhibitory Concentration 50
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Liver / metabolism
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Mice
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Models, Molecular
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Protein Binding
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Protein Structure, Quaternary / drug effects
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Pyrrolidines / chemistry
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Pyrrolidines / metabolism
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Pyrrolidines / pharmacology
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Pyrrolidines / therapeutic use
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Serum Amyloid P-Component / antagonists & inhibitors
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Serum Amyloid P-Component / chemistry
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Serum Amyloid P-Component / metabolism*
Substances
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Carboxylic Acids
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Cross-Linking Reagents
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Pyrrolidines
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R-1-(6-(R-2-carboxypyrrolidin-1-yl)-6-oxohexanoyl)pyrrolidine-2-carboxylic acid
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Serum Amyloid P-Component
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Calcium