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Title: Preclinical Validation of the Heparin-Reactive Peptide p5+14 as a Molecular Imaging Agent for Visceral Amyloidosis

Abstract

Amyloid is a complex pathologic matrix comprised principally of para-crystalline protein fibrils and heparan sulfate proteoglycans. Systemic amyloidoses are rare (~3500 new cases per year in the US); thus, routine diagnosis is often challenging, and effective treatment options are limited, resulting in high morbidity and mortality rates. Glycosaminoglycans contribute inextricably to the formation of amyloid fibrils and foster the deposition of amyloid in tissues. Those present in amyloid deposits are biochemically and electrochemically distinct from glycosaminoglycans found in the plasma membrane and extracellular matrices of healthy tissues due to the presence of a high degree of heparin-like hypersulfation. We have exploited this unique property and evaluated heparin-reactive peptides, such as p5+14. Herein we show efficacious detection of murine systemic amyloid in vivo by using molecular imaging, and the specific targeting of the peptide to major forms of human amyloid in tissue sections. Furthermore, we have demonstrated that the peptide also binds synthetic amyloid fibrils that lack glycosaminoglycans implying that the dense anionic motif present on heparin is mimicked by the amyloid protein fibril itself. These biochemical and functional data support the translation of radiolabeled peptide p5+14 for the clinical imaging of amyloid in patients; thus, providing a novel technique formore » prognostication, patient stratification, and monitoring response to therapy.« less

Authors:
 [1];  [2];  [2];  [3];  [2];  [2];  [2];  [2];  [3];  [4];  [4];  [1]
  1. Univ. of Tennessee Graduate School of Medicine, Knoxville, TN (United States). Dept. of Medicine; Univ. of Tennessee Graduate School of Medicine, Knoxville, TN (United States). Dept. of and Radiology
  2. Univ. of Tennessee Graduate School of Medicine, Knoxville, TN (United States). Dept. of Medicine
  3. Univ. of Tennessee Graduate School of Medicine, Knoxville, TN (United States). Dept. of and Radiology
  4. Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States). Bioscience Division; Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States). Computer Science and Mathematics Division
Publication Date:
Research Org.:
Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)
Sponsoring Org.:
USDOE Laboratory Directed Research and Development (LDRD) Program
OSTI Identifier:
1327576
Grant/Contract Number:  
AC05-00OR22725; R01DK079984
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
Molecules
Additional Journal Information:
Journal Volume: 20; Journal Issue: 5; Journal ID: ISSN 1420-3049
Publisher:
MDPI
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; glycosaminoglycans; amyloidosis; peptide; imaging; modeling; SPECT; p5+14

Citation Formats

Wall, Jonathan, Martin, Emily B., Richey, Tina, Stuckey, Alan C., Macy, Sallie, Wooliver, Craig, Williams, Angela, Foster, James S., McWilliams-Koeppen, Penney, Uberbacher, Ed, Cheng, Xiaolin, and Kennel, Stephen J. Preclinical Validation of the Heparin-Reactive Peptide p5+14 as a Molecular Imaging Agent for Visceral Amyloidosis. United States: N. p., 2015. Web. doi:10.3390/molecules20057657.
Wall, Jonathan, Martin, Emily B., Richey, Tina, Stuckey, Alan C., Macy, Sallie, Wooliver, Craig, Williams, Angela, Foster, James S., McWilliams-Koeppen, Penney, Uberbacher, Ed, Cheng, Xiaolin, & Kennel, Stephen J. Preclinical Validation of the Heparin-Reactive Peptide p5+14 as a Molecular Imaging Agent for Visceral Amyloidosis. United States. doi:10.3390/molecules20057657.
Wall, Jonathan, Martin, Emily B., Richey, Tina, Stuckey, Alan C., Macy, Sallie, Wooliver, Craig, Williams, Angela, Foster, James S., McWilliams-Koeppen, Penney, Uberbacher, Ed, Cheng, Xiaolin, and Kennel, Stephen J. Mon . "Preclinical Validation of the Heparin-Reactive Peptide p5+14 as a Molecular Imaging Agent for Visceral Amyloidosis". United States. doi:10.3390/molecules20057657. https://www.osti.gov/servlets/purl/1327576.
@article{osti_1327576,
title = {Preclinical Validation of the Heparin-Reactive Peptide p5+14 as a Molecular Imaging Agent for Visceral Amyloidosis},
author = {Wall, Jonathan and Martin, Emily B. and Richey, Tina and Stuckey, Alan C. and Macy, Sallie and Wooliver, Craig and Williams, Angela and Foster, James S. and McWilliams-Koeppen, Penney and Uberbacher, Ed and Cheng, Xiaolin and Kennel, Stephen J.},
abstractNote = {Amyloid is a complex pathologic matrix comprised principally of para-crystalline protein fibrils and heparan sulfate proteoglycans. Systemic amyloidoses are rare (~3500 new cases per year in the US); thus, routine diagnosis is often challenging, and effective treatment options are limited, resulting in high morbidity and mortality rates. Glycosaminoglycans contribute inextricably to the formation of amyloid fibrils and foster the deposition of amyloid in tissues. Those present in amyloid deposits are biochemically and electrochemically distinct from glycosaminoglycans found in the plasma membrane and extracellular matrices of healthy tissues due to the presence of a high degree of heparin-like hypersulfation. We have exploited this unique property and evaluated heparin-reactive peptides, such as p5+14. Herein we show efficacious detection of murine systemic amyloid in vivo by using molecular imaging, and the specific targeting of the peptide to major forms of human amyloid in tissue sections. Furthermore, we have demonstrated that the peptide also binds synthetic amyloid fibrils that lack glycosaminoglycans implying that the dense anionic motif present on heparin is mimicked by the amyloid protein fibril itself. These biochemical and functional data support the translation of radiolabeled peptide p5+14 for the clinical imaging of amyloid in patients; thus, providing a novel technique for prognostication, patient stratification, and monitoring response to therapy.},
doi = {10.3390/molecules20057657},
journal = {Molecules},
issn = {1420-3049},
number = 5,
volume = 20,
place = {United States},
year = {2015},
month = {4}
}

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Cited by: 12 works
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Works referenced in this record:

Scalable molecular dynamics with NAMD
journal, January 2005

  • Phillips, James C.; Braun, Rosemary; Wang, Wei
  • Journal of Computational Chemistry, Vol. 26, Issue 16, p. 1781-1802
  • DOI: 10.1002/jcc.20289