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

• Published in: Molecules (Basel, Switzerland) Vol. 20; no. 5; pp. 7657 - 7682
• Main Authors: Wall, Jonathan S, 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
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 27-04-2015; MDPI
• Subjects: 60 APPLIED LIFE SCIENCES; Amino Acid Sequence; Amyloid - chemistry; Amyloid - metabolism; Amyloidogenic Proteins - metabolism; Amyloidosis; Amyloidosis - diagnosis; Animals; Biotinylation; Contrast Media - chemical synthesis; Contrast Media - chemistry; Contrast Media - pharmacology; Enzymes; glycosaminoglycans; Glycosaminoglycans - chemistry; Glycosaminoglycans - metabolism; Heparan sulfate; Heparin - metabolism; Humans; imaging; Interleukin-6 - biosynthesis; Interleukin-6 - genetics; Iodine Radioisotopes - chemistry; Iodine Radioisotopes - pharmacokinetics; Mice; Mice, Inbred BALB C; Mice, Transgenic; modeling; Molecular Imaging - methods; Oligopeptides - chemical synthesis; Oligopeptides - chemistry; Oligopeptides - pharmacology; p5+14; peptide; Peptides; Peptides - chemical synthesis; Peptides - chemistry; Peptides - pharmacology; Positron-Emission Tomography - methods; Protein Binding; Proteins; SPECT; Tomography, Emission-Computed, Single-Photon - methods; United States > US
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules20057657

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.