Targeted pharmacological depletion of serum amyloid P component for treatment of human amyloidosis

• Published in: Nature (London) Vol. 417; no. 6886; pp. 254 - 259
• Main Authors: Pepys, M. B., Herbert, J., Hutchinson, W. L., Tennent, G. A., Lachmann, H. J., Gallimore, J. R., Lovat, L. B., Bartfai, T., Alanine, A., Hertel, C., Hoffmann, T., Jakob-Roetne, R., Norcross, R. D., Kemp, J. A., Yamamura, K., Suzuki, M., Taylor, G. W., Murray, S., Thompson, D., Purvis, A., Kolstoe, S., Wood, S. P., Hawkins, P. N.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 16.05.2002; Nature Publishing; Nature Publishing Group
• Subjects: Alzheimer's disease; Amyloidosis - blood; Amyloidosis - drug therapy; Amyloidosis - metabolism; Animals; Biological and medical sciences; Calcium - metabolism; Carboxylic acids; Carboxylic Acids - chemistry; Carboxylic Acids - metabolism; Carboxylic Acids - pharmacology; Carboxylic Acids - therapeutic use; Cross-Linking Reagents - chemistry; Cross-Linking Reagents - metabolism; Cross-Linking Reagents - pharmacology; Cross-Linking Reagents - therapeutic use; Crystallography, X-Ray; Dimerization; General and cellular metabolism. Vitamins; Humanities and Social Sciences; Humans; Inhibitory Concentration 50; Liver - metabolism; Medical sciences; Mice; Models, Molecular; multidisciplinary; Pharmacology; Pharmacology. Drug treatments; Plasma; Protein Binding; Protein Structure, Quaternary - drug effects; Proteins; Pyrrolidine; Pyrrolidines - chemistry; Pyrrolidines - metabolism; Pyrrolidines - pharmacology; Pyrrolidines - therapeutic use; Science; Science (multidisciplinary); serum amyloid P; Serum Amyloid P-Component - antagonists & inhibitors; Serum Amyloid P-Component - chemistry; Serum Amyloid P-Component - metabolism; Human; Drug; Serum amyloid protein SAP; Rodentia; Metabolic diseases; Enzymopathy; Protein; Vertebrata; Chemotherapy; Biological fixation; Mammalia; Treatment; Mouse; Animal; Amyloidosis; Inhibitor; Mechanism of action
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/417254a

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.