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

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.

• Authors: M B Pepys, J Herbert, W L Hutchinson, G A Tennent, H J Lachmann, J R Gallimore, L B Lovat, T Bartfai, A Alanine, C Hertel, T Hoffmann, R Jakob-Roetne, R D Norcross, J A Kemp, K Yamamura, M Suzuki, G W Taylor, S Murray, D Thompson, A Purvis, S Kolstoe, S P Wood, P N Hawkins
• Journal: Nature (Nature) Vol. 417 Issue 6886 Pg. 254-9 (May 16 2002) ISSN: 0028-0836 [Print] England
• PMID: 12015594 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Carboxylic Acids
• Cross-Linking Reagents
• Pyrrolidines
• R-1-(6-(R-2-carboxypyrrolidin-1-yl)-6-oxohexanoyl)pyrrolidine-2-carboxylic acid
• Serum Amyloid P-Component
• Calcium

Topics

• Amyloidosis (blood, drug therapy, metabolism)
• Animals
• Calcium (metabolism)
• Carboxylic Acids (chemistry, metabolism, pharmacology, therapeutic use)
• Cross-Linking Reagents (chemistry, metabolism, pharmacology, therapeutic use)
• Crystallography, X-Ray
• Dimerization
• Humans
• Inhibitory Concentration 50
• Liver (metabolism)
• Mice
• Models, Molecular
• Protein Binding
• Protein Structure, Quaternary (drug effects)
• Pyrrolidines (chemistry, metabolism, pharmacology, therapeutic use)
• Serum Amyloid P-Component (antagonists & inhibitors, chemistry, metabolism)