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Retro-inversal of intracellular selected ?-amyloid-interacting peptides: implications for a novel Alzheimer's disease treatment

Acerra, Nicola, Kad, Neil M, Griffith, Douglas A, Ott, Stanislav, Crowther, Damian C, Mason, Jody M (2014) Retro-inversal of intracellular selected ?-amyloid-interacting peptides: implications for a novel Alzheimer's disease treatment. Biochemistry, 53 (13). pp. 2101-2111. ISSN 1520-4995. (doi:10.1021/bi5001257) (The full text of this publication is not currently available from this repository. You may be able to access a copy if URLs are provided) (KAR id:42938)

The full text of this publication is not currently available from this repository. You may be able to access a copy if URLs are provided. (Contact us about this Publication)
Official URL
http://dx.doi.org/10.1021/bi5001257

Abstract

The aggregation of ?-amyloid (A?) 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 A?1-42. 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 A?-interacting peptides. This approach has subsequently led to several peptide candidates being further explored as potential treatments for Alzheimer's disease.

Item Type: Article
DOI/Identification number: 10.1021/bi5001257
Subjects: Q Science
Divisions: Faculties > Sciences > School of Biosciences
Depositing User: N. Kad
Date Deposited: 15 Sep 2014 19:39 UTC
Last Modified: 06 May 2020 03:10 UTC
Resource URI: https://kar.kent.ac.uk/id/eprint/42938 (The current URI for this page, for reference purposes)
Kad, Neil M: https://orcid.org/0000-0002-3491-8595
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