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.
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CPHPC efficiently binds to SAP, leading to the dissociation of SAP from bound amyloids and subsequent depletion of SAP levels in the body.
“This compound efficiently binds to SAP, leading to the dissociation of SAP from bound amyloids and subsequent depletion of SAP levels in the body24,62–68.”
From Serum amyloid P secreted by bone marrow adipocytes drives skeletal amyloidosis (2025) · cites this paper as [64]
Several recent studies have reported that CPHPC is also effective in depleting SAP in mice in different disease models.
“However, consistent with our results in mice, several recent studies have reported that this drug is also effective in depleting SAP in mice in different disease models62,64.”
From Serum amyloid P secreted by bone marrow adipocytes drives skeletal amyloidosis (2025) · cites this paper as [64]
CPHPC (miridesap) at a concentration of 5 mg ml−1 in drinking water is an established dose for SAP depletion from the body.
“To examine the effects of CPHPC on age-associated bone changes, male and female mice aged 18 months were treated with CPHPC (miridesap) at a concentration of 5 mg ml−1 in drinking water, which is an established dose for SAP depletion from the body62–65,67,68,84.”
From Serum amyloid P secreted by bone marrow adipocytes drives skeletal amyloidosis (2025) · cites this paper as [64]
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“Our recent finding that mice with targeted deletion of the SAP gene show retarded and reduced induction of experimental reactive systemic (AA type) amyloidosis confirmed that SAP does indeed contribute to pathogenesis of amyloidosi”
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BackgroundSelf-citation
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“Binding and elimination for SAP-CPHPC complex Although the complex of the pentameric SAP molecule with CPHPC comprises two SAP molecules crosslinked by five drug molecules when sufficient drug is available, very rapid clearance of circulating SAP starts when there is just one mole of drug available per mole of pentame…”
BackgroundMethodResultInfluentialSerum amyloid P secreted by bone marrow adipocytes drives skeletal amyloidosis
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Genetic evidence for serum amyloid P component as a drug target in neurodegenerative disorders
Schmidt, A. F., Finan, C., Chopade, S., Ellmerich, S., Rossor, M. N., Hingorani, A. D., & Pepys, M. B. (2024) · Open Biology · doi:10.1098/rsob.230419 · Cited by 11 · see citing works
“Fortunately, the experimental drug miridesap (CPHPC; hexanoyl bis-D-proline; ( R )-1-[6-[( R )-2-carboxypyrrolidin-1-yl]-6-oxo- hexanoyl]pyrrolidine-2-carboxylic acid) [65] safely provides extremely effective SAP depletion.”
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“Human SAP (2 mg) was administered SQ 18 h before the injection of fungi thus providing serum levels of SAP approximating the human serum concentration of SAP [22].”
BackgroundMethodInfluential
- Authors
- 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., & Hawkins, P. N.
- Affiliations
- The Royal Free Hospital (GB)
- F. Hoffmann-La Roche AG (CH)
- Institute of Molecular Embryology and Genetics, Kumamoto University (JP)
- Imperial College London (GB)
- University of Southampton (GB)
- Corresponding author
- Pepys, M. B.
- ORCID
- Venue
- Nature
- Published
- 2002-05
- Volume
- 417
- Issue
- 6886
- Pages
- 254-259
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2144086680
- Cited by
- 540
- References
- 6
- Citations by year
- 2026: 5 · 2025: 5 · 2024: 6 · 2023: 7 · 2022: 15 · 2021: 9 · 2020: 11 · 2019: 14 · 2018: 18 · 2017: 12 · 2016: 22 · 2015: 20 · 2014: 22 · 2013: 23 · 2012: 40
- FWCI
- 17.27
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- ePrints Soton (University of Southampton) (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Amyloidosis: Diagnosis, Treatment, Outcomes
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Prion Diseases and Protein Misfolding
- Keywords
- serum amyloid P component, amyloidosis, amyloid fibrils, systemic amyloidosis, Alzheimer's disease, type 2 diabetes, amyloid deposits
- MeSH terms
- Serum Amyloid P-Component, Amyloidosis, Animals, Calcium, Carboxylic Acids, Cross-Linking Reagents, Humans, Liver, Models, Molecular, Protein Binding, Pyrrolidines, Crystallography, X-Ray, Dimerization, Inhibitory Concentration 50, Protein Structure, Quaternary, Mice
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