Transthyretin Mimetics as Anti-β-Amyloid Agents: A Comparison of Peptide and Protein Approaches.

Autor: Pate KM; Department of Chemical and Biological Engineering, University of Wisconsin - Madison, 1415 Engineering Drive, Madison, WI, 53706, USA., Kim BJ; Department of Chemical and Biological Engineering, University of Wisconsin - Madison, 1415 Engineering Drive, Madison, WI, 53706, USA., Shusta EV; Department of Chemical and Biological Engineering, University of Wisconsin - Madison, 1415 Engineering Drive, Madison, WI, 53706, USA., Murphy RM; Department of Chemical and Biological Engineering, University of Wisconsin - Madison, 1415 Engineering Drive, Madison, WI, 53706, USA.
Jazyk: angličtina
Zdroj: ChemMedChem [ChemMedChem] 2018 May 08; Vol. 13 (9), pp. 968-979. Date of Electronic Publication: 2018 Apr 16.
DOI: 10.1002/cmdc.201800031
Abstrakt: β-Amyloid (Aβ) aggregation is causally linked to neuronal pathology in Alzheimer's disease; therefore, several small molecules, antibodies, and peptides have been tested as anti-Aβ agents. We developed two compounds based on the Aβ-binding domain of transthyretin (TTR): a cyclic peptide cG8 and an engineered protein mTTR, and compared them for therapeutically relevant properties. Both mTTR and cG8 inhibit fibrillogenesis of Aβ, with mTTR inhibiting at a lower concentration than cG8. Both inhibit aggregation of amylin but not of α-synuclein. They both bind more Aβ aggregates than monomer, and neither disaggregates preformed fibrils. cG8 retained more of its activity in the presence of biological materials and was more resistant to proteolysis than mTTR. We examined the effect of mTTR or cG8 on Aβ binding to human neurons. When mTTR was co-incubated with Aβ under oligomer-forming conditions, Aβ morphology was drastically changed and Aβ-cell deposition significantly decreased. In contrast, cG8 did not affect morphology but decreased the amount of Aβ deposited. These results provide guidance for further evolution of TTR-mimetic anti-amyloid agents.
(© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)
Databáze: MEDLINE
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