title: Combining intracellular selection with protein-fragment complementation to derive Aβ interacting peptides.
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. 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.
authors.affiliation: The School of Biological Sciences, University of Essex, Wivenhoe Park, Colchester CO4 3SQ, UK.
authors.forename: Nicola
authors.initials: N
authors.lastname: Acerra
authors.forename: Neil M
authors.initials: NM
authors.lastname: Kad
authors.forename: Jody M
authors.initials: JM
authors.lastname: Mason
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism; D019151:Peptide Library
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D019151:Peptide Library
keywords: Alzheimer's disease; peptide interactions; protein-fragment complementation, β-sheets; β-amyloid