Preclinical Validation of the Heparin-Reactive Peptide p5+14 as a Molecular Imaging Agent for Visceral Amyloidosis.
Amyloid is a complex pathologic matrix comprised principally of paracrystalline protein fibrils and heparan sulfate proteoglycans. Systemic amyloid diseases are rare, thus, routine diagnosis is often challenging. The glycosaminoglycans ubiquitously present in amyloid deposits are biochemically and electrochemically distinct from those found in the healthy tissues due to the high degree of sulfation. We have exploited this unique property and evaluated heparin-reactive peptides, such as p5+14, as novel agents for specifically targeting and imaging amyloid. Herein, we demonstrate that radiolabeled p5+14 effectively bound murine AA amyloid in vivo by using molecular imaging. Biotinylated peptide also reacted with the major forms of human amyloid in tissue sections as evidenced immunohistochemically. 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.
Department of Medicine, University of Tennessee Graduate School of Medicine, Knoxville, TN 37920, USA. jwall@utmck.edu.|Department of and Radiology, University of Tennessee Graduate School of Medicine, Knoxville, TN 37920, USA. jwall@utmck.edu.
Jonathan S
JS
Wall
Department of Medicine, University of Tennessee Graduate School of Medicine, Knoxville, TN 37920, USA. emartin@utmck.edu.
Emily B
EB
Martin
Department of Medicine, University of Tennessee Graduate School of Medicine, Knoxville, TN 37920, USA. trichey@utmck.edu.
Tina
T
Richey
Department of and Radiology, University of Tennessee Graduate School of Medicine, Knoxville, TN 37920, USA. astuckey@utmck.edu.
Alan C
AC
Stuckey
Department of Medicine, University of Tennessee Graduate School of Medicine, Knoxville, TN 37920, USA. smacy@utmck.edu.
Sallie
S
Macy
Department of Medicine, University of Tennessee Graduate School of Medicine, Knoxville, TN 37920, USA. dwooliver@utmck.edu.
Craig
C
Wooliver
Department of Medicine, University of Tennessee Graduate School of Medicine, Knoxville, TN 37920, USA. awilliam@utmck.edu.
Angela
A
Williams
Department of Medicine, University of Tennessee Graduate School of Medicine, Knoxville, TN 37920, USA. jfoster3@uthsc.edu.
James S
JS
Foster
Department of and Radiology, University of Tennessee Graduate School of Medicine, Knoxville, TN 37920, USA. PMKoeppen@utmck.edu.
Penney
P
McWilliams-Koeppen
Bioscience Division, Oak Ridge National Laboratory, Oak Ridge, TN 37831, USA. uberbacherec@ornl.gov.|Computer Science and Mathematics Division, Oak Ridge National Laboratory, Oak Ridge, TN 37831, USA. uberbacherec@ornl.gov.
Ed
E
Uberbacher
Bioscience Division, Oak Ridge National Laboratory, Oak Ridge, TN 37831, USA. chengx@ornl.gov.|Computer Science and Mathematics Division, Oak Ridge National Laboratory, Oak Ridge, TN 37831, USA. chengx@ornl.gov.
Xiaolin
X
Cheng
Department of Medicine, University of Tennessee Graduate School of Medicine, Knoxville, TN 37920, USA. skennel@utmck.edu.|Department of and Radiology, University of Tennessee Graduate School of Medicine, Knoxville, TN 37920, USA. skennel@utmck.edu.
Stephen J
SJ
Kennel
D000595:Amino Acid Sequence; D000682:Amyloid / Q000737:chemistry / Q000378:metabolism*; D058227:Amyloidogenic Proteins / Q000378:metabolism; D000686:Amyloidosis / Q000175:diagnosis*; D000818:Animals; D019921:Biotinylation; D003287:Contrast Media / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006025:Glycosaminoglycans / Q000737:chemistry / Q000378:metabolism; D006493:Heparin / Q000378:metabolism; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics; D007457:Iodine Radioisotopes / Q000737:chemistry / Q000493:pharmacokinetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D057054:Molecular Imaging / Q000379:methods; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D049268:Positron-Emission Tomography / Q000379:methods*; D011485:Protein Binding; D015899:Tomography, Emission-Computed, Single-Photon / Q000379:methods*
D000682:Amyloid; D058227:Amyloidogenic Proteins; D003287:Contrast Media; D006025:Glycosaminoglycans; C508600:IL6 protein, human; D015850:Interleukin-6; D007457:Iodine Radioisotopes; D009842:Oligopeptides; D010455:Peptides; C000606133:peptide p5 plus 14; D006493:Heparin