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

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. A. Kemp, K. Yamamura, M. Suzuki, G. W. Taylor, S. Murray, D. Thompson, A. Purvis, S. Kolstoe, S. P. Wood and P. N. Hawkins
Additional contact information
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
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

Nature, 2002, vol. 417, issue 6886, 254-259

Abstract: 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.

Date: 2002
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DOI: 10.1038/417254a

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