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Combining intracellular selection with protein-fragment complementation to derive A interacting peptides

Acerra, Nicola and Kad, Neil M and Mason, Jody M (2013) 'Combining intracellular selection with protein-fragment complementation to derive A interacting peptides.' Protein Engineering Design and Selection. ISSN 1741-0126

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Abstract

Aggregation of the β-amyloid (Aβ) peptide into toxic oligomers is considered the primary event in the pathogenesis of Alzheimer's disease. Previously generated peptides and mimetics designed to bind to amyloid fibrils have encountered problems in solubility, protease susceptibility and the population of small soluble toxic oligomers oligomers. We present a new method that opens the possibility of deriving new amyloid inhibitors. The intracellular protein-fragment complementation assay (PCA) approach uses a semi-rational design approach to generate peptides capable of binding to Aβ. Peptide libraries are based on Aβ regions responsible for instigating amyloidosis, with screening and selection occurring entirely inside Escherichia coli. Successfully selected peptides must therefore bind Aβ and recombine an essential enzyme while permitting bacterial cell survival. No assumptions are made regarding the mechanism of action for selected binders. Biophysical characterisation demonstrates that binding induces a noticeable reduction in amyloid. Therefore, this amyloid-PCA approach may offer a new pathway for the design of effective inhibitors against the formation of amyloid in general.

Item Type: Article
Uncontrolled Keywords: Alzheimer's disease; β-amyloid; peptide interactions; protein-fragment complementation, β-sheets
Subjects: Q Science > QH Natural history > QH301 Biology
Divisions: Faculty of Science and Health > Biological Sciences, School of
Depositing User: Jim Jamieson
Date Deposited: 06 Jun 2013 14:19
Last Modified: 16 Dec 2014 11:14
URI: http://repository.essex.ac.uk/id/eprint/6866

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