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

Mark B. Pepys, J. Herbert, Winston L. Hutchinson, Glenys A. Tennent, H. J. Lachmann, J. Ruth 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, Grham W. Taylor, S. Murray, Darren Thompson, A. PurvisSimon Kolstoe, Stephen P. Wood, Philip N. Hawkins

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)254-259
Issue number6886
Publication statusPublished - 16 May 2002


  • Amyloidosis
  • Animals
  • Calcium
  • Carboxylic Acids
  • Cross-Linking Reagents
  • Crystallography, X-Ray
  • Dimerization
  • Humans
  • Inhibitory Concentration 50
  • Liver
  • Mice
  • Models, Molecular
  • Protein Binding
  • Protein Structure, Quaternary
  • Pyrrolidines
  • Serum Amyloid P-Component


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