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

Author

Listed:
  • M. B. Pepys

    (Royal Free and University College Medical School)

  • J. Herbert

    (Royal Free and University College Medical School)

  • W. L. Hutchinson

    (Royal Free and University College Medical School)

  • G. A. Tennent

    (Royal Free and University College Medical School)

  • H. J. Lachmann

    (Royal Free and University College Medical School)

  • J. R. Gallimore

    (Royal Free and University College Medical School)

  • L. B. Lovat

    (Royal Free and University College Medical School)

  • T. Bartfai

    (F Hoffmann-La Roche Ltd
    The Scripps Research Institute)

  • A. Alanine

    (F Hoffmann-La Roche Ltd)

  • C. Hertel

    (F Hoffmann-La Roche Ltd)

  • T. Hoffmann

    (F Hoffmann-La Roche Ltd)

  • R. Jakob-Roetne

    (F Hoffmann-La Roche Ltd)

  • R. D. Norcross

    (F Hoffmann-La Roche Ltd)

  • J. A. Kemp

    (F Hoffmann-La Roche Ltd)

  • K. Yamamura

    (Kumamoto University)

  • M. Suzuki

    (Kumamoto University)

  • G. W. Taylor

    (Imperial College School of Medicine)

  • S. Murray

    (Imperial College School of Medicine)

  • D. Thompson

    (University of Southampton)

  • A. Purvis

    (University of Southampton)

  • S. Kolstoe

    (University of Southampton)

  • S. P. Wood

    (University of Southampton)

  • P. N. Hawkins

    (Royal Free and University College Medical School)

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.

Suggested Citation

  • 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., 2002. "Targeted pharmacological depletion of serum amyloid P component for treatment of human amyloidosis," Nature, Nature, vol. 417(6886), pages 254-259, May.
    • Handle: RePEc:nat:nature:v:417:y:2002:i:6886:d:10.1038_417254a
    DOI: 10.1038/417254a
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    Cited by:

    1. Vincent Kwok Lim Lam & Ronald Ching Wan Ma & Heung Man Lee & Cheng Hu & Kyong Soo Park & Hiroto Furuta & Ying Wang & Claudia Ha Ting Tam & Xueling Sim & Daniel Peng-Keat Ng & Jianjun Liu & Tien-Yin Wo, 2013. "Genetic Associations of Type 2 Diabetes with Islet Amyloid Polypeptide Processing and Degrading Pathways in Asian Populations," PLOS ONE, Public Library of Science, vol. 8(6), pages 1-12, June.

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