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

Mark B. Pepys; J. Herbert; Winston L. Hutchinson; Glenys A. Tennent; H. J. Lachmann; J. Ruth 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; Grham W. Taylor; S. Murray; Darren Thompson; A. Purvis; Simon Kolstoe; Stephen P. Wood; Philip N. Hawkins

doi:10.1038/417254a

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

Mark B. Pepys, J. Herbert, Winston L. Hutchinson, Glenys A. Tennent, H. J. Lachmann, J. Ruth 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, Grham W. Taylor, S. Murray, Darren Thompson, A. PurvisSimon Kolstoe, Stephen P. Wood, Philip N. Hawkins

Institute of Life Sciences and Healthcare

University College London

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Pages (from-to)	254-259
Journal	Nature
Volume	417
Issue number	6886
DOIs	https://doi.org/10.1038/417254a
Publication status	Published - 16 May 2002

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Amyloidosis
Animals
Calcium
Carboxylic Acids
Cross-Linking Reagents
Crystallography, X-Ray
Dimerization
Humans
Inhibitory Concentration 50
Liver
Mice
Models, Molecular
Protein Binding
Protein Structure, Quaternary
Pyrrolidines
Serum Amyloid P-Component

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10.1038/417254a

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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., ... Hawkins, P. N. (2002). Targeted pharmacological depletion of serum amyloid P component for treatment of human amyloidosis. Nature, 417(6886), 254-259. https://doi.org/10.1038/417254a

@article{b99f95c8a6084180bbf7f4ca88cf135c,

title = "Targeted pharmacological depletion of serum amyloid P component for treatment of human amyloidosis",

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.",

keywords = "Amyloidosis, Animals, Calcium, Carboxylic Acids, Cross-Linking Reagents, Crystallography, X-Ray, Dimerization, Humans, Inhibitory Concentration 50, Liver, Mice, Models, Molecular, Protein Binding, Protein Structure, Quaternary, Pyrrolidines, Serum Amyloid P-Component",

author = "Pepys, \{Mark B.\} and J. Herbert and Hutchinson, \{Winston L.\} and Tennent, \{Glenys A.\} and Lachmann, \{H. J.\} and Gallimore, \{J. Ruth\} and Lovat, \{L. B.\} and T. Bartfai and A. Alanine and C. Hertel and T. Hoffmann and R. Jakob-Roetne and Norcross, \{R. D.\} and Kemp, \{J. A.\} and K. Yamamura and M. Suzuki and Taylor, \{Grham W.\} and S. Murray and Darren Thompson and A. Purvis and Simon Kolstoe and Wood, \{Stephen P.\} and Hawkins, \{Philip N.\}",

year = "2002",

month = may,

day = "16",

doi = "10.1038/417254a",

language = "English",

volume = "417",

pages = "254--259",

journal = "Nature",

issn = "0028-0836",

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Pepys, MB, Herbert, J, Hutchinson, WL, Tennent, GA, Lachmann, HJ, Gallimore, JR, Lovat, LB, Bartfai, T, Alanine, A, Hertel, C, Hoffmann, T, Jakob-Roetne, R, Norcross, RD, Kemp, JA, Yamamura, K, Suzuki, M, Taylor, GW, Murray, S, Thompson, D, Purvis, A, Kolstoe, S , Wood, SP & Hawkins, PN 2002, 'Targeted pharmacological depletion of serum amyloid P component for treatment of human amyloidosis', Nature, vol. 417, no. 6886, pp. 254-259. https://doi.org/10.1038/417254a

TY - JOUR

T1 - Targeted pharmacological depletion of serum amyloid P component for treatment of human amyloidosis

AU - Pepys, Mark B.

AU - Herbert, J.

AU - Hutchinson, Winston L.

AU - Tennent, Glenys A.

AU - Lachmann, H. J.

AU - Gallimore, J. Ruth

AU - Lovat, L. B.

AU - Bartfai, T.

AU - Alanine, A.

AU - Hertel, C.

AU - Hoffmann, T.

AU - Jakob-Roetne, R.

AU - Norcross, R. D.

AU - Kemp, J. A.

AU - Yamamura, K.

AU - Suzuki, M.

AU - Taylor, Grham W.

AU - Murray, S.

AU - Thompson, Darren

AU - Purvis, A.

AU - Kolstoe, Simon

AU - Wood, Stephen P.

AU - Hawkins, Philip N.

PY - 2002/5/16

Y1 - 2002/5/16

N2 - 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.

AB - 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.

KW - Amyloidosis

KW - Animals

KW - Calcium

KW - Carboxylic Acids

KW - Cross-Linking Reagents

KW - Crystallography, X-Ray

KW - Dimerization

KW - Humans

KW - Inhibitory Concentration 50

KW - Liver

KW - Mice

KW - Models, Molecular

KW - Protein Binding

KW - Protein Structure, Quaternary

KW - Pyrrolidines

KW - Serum Amyloid P-Component

U2 - 10.1038/417254a

DO - 10.1038/417254a

M3 - Article

C2 - 12015594

SN - 0028-0836

VL - 417

SP - 254

EP - 259

JO - Nature

JF - Nature

IS - 6886

ER -

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

Abstract

UN SDGs

Keywords

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