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

Academic Article
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Overview

authors

  • Pepys, M. B.
  • Herbert, J.
  • Hutchinson, W. L.
  • Tennent, G. A.
  • Lachmann, H. J.
  • Gallimore, J. R.
  • Lovat, L. B.
  • Bartfai, Tamas
  • Alanine, A.
  • Hertel, C.
  • Hoffmann, T.
  • Jakob-Roetne, R.
  • Norcross, R. D.
  • Kemp, J. A.
  • Yamamura, K.
  • Suzuki, M.
  • Taylor, G. W.
  • Murray, Sarah
  • Thompson, D.
  • Purvis, A.
  • Kolstoe, S.
  • Wood, S. P.
  • Hawkins, P. N.

publication date

  • May 2002

journal

  • Nature  Journal

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.

subject areas

  • 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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Identity

International Standard Serial Number (ISSN)

  • 0028-0836

Digital Object Identifier (DOI)

  • 10.1038/417254a

PubMed ID

  • 12015594
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Additional Document Info

start page

  • 254

end page

  • 259

volume

  • 417

issue

  • 6886

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