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Retro-inversal of Intracellular Selected β-Amyloid-Interacting Peptides: Implications for a Novel Alzheimer’s Disease Treatment

Acerra, Nicola and Kad, Neil M and Griffith, Douglas A and Ott, Stanislav and Crowther, Damian C and Mason, Jody M (2014) 'Retro-inversal of Intracellular Selected β-Amyloid-Interacting Peptides: Implications for a Novel Alzheimer’s Disease Treatment.' Biochemistry, 53 (13). pp. 2101-2111. ISSN 0006-2960

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The aggregation of β-amyloid (Aβ) into toxic oligomers is a hallmark of Alzheimer’s disease pathology. Here we present a novel approach for the development of peptides capable of preventing amyloid aggregation based upon the previous selection of natural all-l peptides that bind Aβ1–42. Using an intracellular selection system, successful library members were further screened via competition selection to identify the most effective peptides capable of reducing amyloid levels. To circumvent potential issues arising from stability and protease action for these structures, we have replaced all l residues with d residues and inverted the sequence. These retro-inverso (RI) peptide analogues therefore encompass reversed sequences that maintain the overall topological order of the native peptides. Our results demonstrate that efficacy in blocking and reversing amyloid formation is maintained while introducing desirable properties to the peptides. Thioflavin-T assays, circular dichroism, and oblique angle fluorescence microscopy collectively indicate that RI peptides can reduce amyloid load, while 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays demonstrate modest reductions in cell toxicity. These conclusions are reinforced using Drosophila melanogaster studies to monitor pupal hatching rates and fly locomotor activity in the presence of RI peptides delivered via RI–trans-activating transcriptional activator peptide fusions. We demonstrate that the RI–protein fragment complementation assay approach can be used as a generalized method for deriving Aβ-interacting peptides. This approach has subsequently led to several peptide candidates being further explored as potential treatments for Alzheimer’s disease.

Item Type: Article
Subjects: Q Science > QH Natural history > QH301 Biology
Divisions: Faculty of Science and Health > Life Sciences, School of
SWORD Depositor: Elements
Depositing User: Elements
Date Deposited: 23 Sep 2014 09:58
Last Modified: 08 Jan 2022 00:31

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