Targeted pharmacological depletion of serum amyloid P component (SAP) 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, Suzuki, M, Taylor, G W, Murray, S, Thompson, D, Purvis, A, Kolstoe, S, Wood, S P and Hawkins, P N (2002) Targeted pharmacological depletion of serum amyloid P component (SAP) for treatment of human amyloidosis. Nature, 417. pp. 254-259. ISSN 0028-0836

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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.

Item Type: Article
Additional Information: Thompson carried out all the structural work with the drug bound to the protein, a major part of this paper, and played a major role in the design of the compound from his native structure.
Schools and Departments: School of Life Sciences > Biochemistry
Depositing User: EPrints Services
Date Deposited: 06 Feb 2012 21:13
Last Modified: 30 Nov 2012 17:10
URI: http://sro.sussex.ac.uk/id/eprint/30364
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