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.
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This work was supported by grants from the Medical Research Council and The Wellcome Trust to M.B.P., P.N.H. and S.P.W., by National Health Service R & D Funds, and by many donations of patients, relatives and friends to the Amyloidosis Research Fund. M.B.P. conceived the idea of inhibition of SAP binding for therapy of amyloidosis, devised the screening assay, originated and directed the project and wrote the paper; J.H., W.L.H., G.A.T., J.R.G. and L.B.L. performed the experimental work and protein assays in the Pepys laboratory; T.B. and J.A.K. supervised the project within Roche; R.J.-R., R.D.N., A.A., C.H. and T.H. designed and synthesized the inhibitor molecules and evaluated them in vitro; K.Y. and M.S. provided the human SAP transgenic mouse line; G.W.T. and S.M. performed the ex vivo drug assays; S.P.W., D.T., S.K. and A.P. crystallized the SAP–drug complex and solved its structure; P.N.H. contributed to all aspects of the work in the Pepys laboratory and devised and supervised the clinical study, which was conducted by H.J.L. We thank R. Zell, C. Jenny (kilolab), A. FerRo, P. Keller (galenics), R. Strobel, E. Gocke, B. Schläppi (toxicology), D. Schwab, B. Levet-Trafit, J. Huwyler, S. Poli (pharmacokinetics), P. Williams, U. Widmer, Q. Branca and G. Adam for their contributions, S. Madhoo and D. Gopaul for care of the patients and the SAP scintigraphy studies, M. Botto for help in breeding transgenic mice, and E. Jones for preparation of the manuscript.
Funding: Work conducted within Roche was funded entirely by F. Hoffmann-La Roche Ltd, which also provided minor running costs and loan of the gamma camera to the Pepys laboratory.
Employment: Authors identified as Roche personnel were employed by Roche while engaged in the project.
Personal financial interests: M.B.P. was consultant to Roche regarding SAP and amyloidosis for the duration of the project, prior to the clinical studies. M.B.P. is the inventor on the patent, cited in the paper, regarding inhibitors of SAP for treatment of amyloidosis. This patent is now owned by UCL. The patents on CPHPC and related compounds are held by Roche with some of their employees named as inventors. Roche retain all rights to commercial exploitation of CPHPC for treatment of Alzheimer's disease and diabetes but has granted an exclusive licence to FreeMedic PLC, the commercial arm of the Royal Free Campus of Royal Free and University College Medical School, for development of CPHPC for other indications.
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