Specific Amyloid Binding of Polybasic Peptides In Vivo Is Retained by ß-Sheet Conformers but Lost in the Disrupted Coil and All D-Amino Acid Variants.
Mol Imaging Biol
; 19(5): 714-722, 2017 Oct.
Article
en En
| MEDLINE
| ID: mdl-28229334
ABSTRACT
PURPOSE:
The heparin-reactive, helical peptide p5 is an effective amyloid imaging agent in mice with systemic amyloidosis. Analogs of p5 with modified secondary structure characteristics exhibited altered binding to heparin, synthetic amyloid fibrils, and amyloid extracts in vitro. Herein, we further study the effects of peptide helicity and chirality on specific amyloid binding using a mouse model of systemic inflammation-associated (AA) amyloidosis. PROCEDURES Peptides with disrupted helical structure [p5(coil) and p5(Pro3)], with an extended sheet conformation [p5(sheet)] or an all-D enantiomer [p5(D)], were chemically synthesized, radioiodinated, and their biodistribution studied in WT mice as well as transgenic animals with severe systemic AA amyloidosis. Peptide binding was assessed qualitatively by using small animal single-photon emission computed tomography/x-ray computed tomography imaging and microautoradiography and quantitatively using tissue counting.RESULTS:
Peptides with reduced helical propensity, p5(coil) and p5(Pro3), exhibited significantly reduced binding to AA amyloid-laden organs. In contrast, peptide p5(D) was retained by non-amyloid-related ligands in the liver and kidneys of both WT and AA mice, but it also bound AA amyloid in the spleen. The p5(sheet) peptide specifically bound AA amyloid in vivo and was not retained by healthy tissues in WT animals.CONCLUSIONS:
Modification of amyloid-targeting peptides using D-amino acids should be performed cautiously due to the introduction of unexpected secondary pharmacologic effects. Peptides that adopt a helical structure, to align charged amino acid side chains along one face, exhibit specific reactivity with amyloid; however, polybasic peptides with a propensity for ß-sheet conformation are also amyloid-reactive and may yield a novel class of amyloid-targeting agents for imaging and therapy.Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Péptidos
/
Aminoácidos
/
Amiloide
/
Mutación
Tipo de estudio:
Prognostic_studies
Límite:
Animals
Idioma:
En
Revista:
Mol Imaging Biol
Asunto de la revista:
BIOLOGIA MOLECULAR
/
DIAGNOSTICO POR IMAGEM
Año:
2017
Tipo del documento:
Article
País de afiliación:
Estados Unidos