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Nature. 2002 May 16;417(6886):231-3.
Targeted pharmacological depletion of serum amyloid P component for treatment of human amyloidosis.
Pepys MB,
Herbert J,
Hutchinson WL,
Tennent GA,
Lachmann HJ,
Gallimore JR,
Lovat LB,
Bartfai T,
Alanine A,
Hertel C,
Hoffmann T,
Jakob-Roetne R,
Norcross RD,
Kemp JA,
Yamamura K,
Suzuki M,
Taylor GW,
Murray S,
Thompson D,
Purvis A,
Kolstoe S,
Wood SP,
Hawkins PN.
Centre for Amyloidosis and Acute Phase Proteins, Department of Medicine, Royal Free and University College Medical School, London NW3 2PF, UK. m.pepys@rfc.ucl.ac.uk
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.
PMID: 12015594 [PubMed - indexed for MEDLINE]