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

Journal Article · · Molecules
 [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
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.
Research Organization:
Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States)
Sponsoring Organization:
ORNL LDRD Seed-Money
Grant/Contract Number:
AC05-00OR22725
OSTI ID:
1327576
Journal Information:
Molecules, Journal Name: Molecules Journal Issue: 5 Vol. 20; ISSN MOLEFW; ISSN 1420-3049
Publisher:
MDPICopyright Statement
Country of Publication:
United States
Language:
English

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Cited By (6)

Secondary structure propensity and chirality of the amyloidophilic peptide p5 and its analogues impacts ligand binding - In vitro characterization journal December 2016
Comparative evaluation of p5+14 with SAP and peptide p5 by dual-energy SPECT imaging of mice with AA amyloidosis journal March 2016
A Peptide-Fc Opsonin with Pan-Amyloid Reactivity journal September 2017
Structural Insight into IAPP‐Derived Amyloid Inhibitors and Their Mechanism of Action journal January 2020
Structural Insight into IAPP‐Derived Amyloid Inhibitors and Their Mechanism of Action journal January 2020
Bifunctional amyloid-reactive peptide promotes binding of antibody 11-1F4 to diverse amyloid types and enhances therapeutic efficacy journal October 2018

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