Targeted pharmacological depletion of serum amyloid P component for treatment of human amyloidosis.
Pepys, M. B. *; Herbert, J. *; Hutchinson, W. L. *; Tennent, G. A. *; Lachmann, H. J. *; Gallimore, J. R. *; Lovat, L. B. *; Bartfai, T. +++; Alanine, A. +; Hertel, C. +; Hoffmann, T. +; Jakob-Roetne, R. +; Norcross, R. D. +; Kemp, J. A. +; Yamamura, K. [S]; Suzuki, M. [S]; Taylor, G. W. [//]; Murray, S. [//]; Thompson, D. [P]; Purvis, A. [P]; Kolstoe, S. [P]; Wood, S. P. [P]; Hawkins, P. N. *
[Article]
Nature.
417(6886):254-259, May 16, 2002.
(Format: HTML)
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.
(C) 2002 Nature Publishing Group