title: 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.affiliation: 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
authors.forename: M B
authors.initials: MB
authors.lastname: Pepys
authors.forename: J
authors.initials: J
authors.lastname: Herbert
authors.forename: W L
authors.initials: WL
authors.lastname: Hutchinson
authors.forename: G A
authors.initials: GA
authors.lastname: Tennent
authors.forename: H J
authors.initials: HJ
authors.lastname: Lachmann
authors.forename: J R
authors.initials: JR
authors.lastname: Gallimore
authors.forename: L B
authors.initials: LB
authors.lastname: Lovat
authors.forename: T
authors.initials: T
authors.lastname: Bartfai
authors.forename: A
authors.initials: A
authors.lastname: Alanine
authors.forename: C
authors.initials: C
authors.lastname: Hertel
authors.forename: T
authors.initials: T
authors.lastname: Hoffmann
authors.forename: R
authors.initials: R
authors.lastname: Jakob-Roetne
authors.forename: R D
authors.initials: RD
authors.lastname: Norcross
authors.forename: J A
authors.initials: JA
authors.lastname: Kemp
authors.forename: K
authors.initials: K
authors.lastname: Yamamura
authors.forename: M
authors.initials: M
authors.lastname: Suzuki
authors.forename: G W
authors.initials: GW
authors.lastname: Taylor
authors.forename: S
authors.initials: S
authors.lastname: Murray
authors.forename: D
authors.initials: D
authors.lastname: Thompson
authors.forename: A
authors.initials: A
authors.lastname: Purvis
authors.forename: S
authors.initials: S
authors.lastname: Kolstoe
authors.forename: S P
authors.initials: SP
authors.lastname: Wood
authors.forename: P N
authors.initials: PN
authors.lastname: Hawkins
mesh_terms: D000686:Amyloidosis / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002264:Carboxylic Acids / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D003432:Cross-Linking Reagents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D018360:Crystallography, X-Ray; D019281:Dimerization; D006801:Humans; D020128:Inhibitory Concentration 50; D008099:Liver / Q000378:metabolism; D051379:Mice; D008958:Models, Molecular; D011485:Protein Binding; D020836:Protein Structure, Quaternary / Q000187:drug effects; D011759:Pyrrolidines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D000683:Serum Amyloid P-Component / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*
chemical_list: D002264:Carboxylic Acids; D003432:Cross-Linking Reagents; D011759:Pyrrolidines; C455899:R-1-(6-(R-2-carboxypyrrolidin-1-yl)-6-oxohexanoyl)pyrrolidine-2-carboxylic acid; D000683:Serum Amyloid P-Component; D002118:Calcium