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


ABSTRACT: ?-Amyloid (A?) aggregation is causally linked to neuronal pathology in Alzheimer's disease; therefore, several small molecules, antibodies, and peptides have been tested as anti-A? agents. We developed two compounds based on the A?-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 A?, with mTTR inhibiting at a lower concentration than cG8. Both inhibit aggregation of amylin but not of ?-synuclein. They both bind more A? 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 A? binding to human neurons. When mTTR was co-incubated with A? under oligomer-forming conditions, A? morphology was drastically changed and A?-cell deposition significantly decreased. In contrast, cG8 did not affect morphology but decreased the amount of A? deposited. These results provide guidance for further evolution of TTR-mimetic anti-amyloid agents.

SUBMITTER: Pate KM 

PROVIDER: S-EPMC5991081 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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

Pate Kayla M KM   Kim Brandon J BJ   Shusta Eric V EV   Murphy Regina M RM  

ChemMedChem 20180416 9


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  ...[more]

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