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Intracellular selection of peptide inhibitors that target disulphide-bridged A?42 oligomers

Acerra, Nicola, Kad, Neil M, Cheruvara, Harish, Mason, Jody M (2014) Intracellular selection of peptide inhibitors that target disulphide-bridged A?42 oligomers. Protein science : a publication of the Protein Society, 23 (9). pp. 1262-1274. E-ISSN 1469-896X. (doi:10.1002/pro.2509) (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:42936)

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/10.1002/pro.2509

Abstract

The ?-amyloid (A?) peptide aggregates into a number of soluble and insoluble forms, with soluble oligomers thought to be the primary factor implicated in Alzheimer's disease pathology. As a result, a wide range of potential aggregation inhibitors have been developed. However, in addition to problems with solubility and protease susceptibility, many have inadvertently raised the concentration of these soluble neurotoxic species. Sandberg et al. previously reported a ?-hairpin stabilized variant of A?42 that results from an intramolecular disulphide bridge (A21C/A31C; A?42cc ), which generates highly toxic oligomeric species incapable of converting into mature fibrils. Using an intracellular protein-fragment complementation (PCA) approach, we have screened peptide libraries using E. coli that harbor an oxidizing environment to permit cytoplasmic disulphide bond formation. Peptides designed to target either the first or second ?-strand have been demonstrated to bind to A?42cc , lower amyloid cytotoxicity, and confer bacterial cell survival. Peptides have consequently been tested using wild-type A?42 via ThT binding assays, circular dichroism, MTT cytotoxicity assays, fluorescence microscopy, and atomic force microscopy. Results demonstrate that amyloid-PCA selected peptides function by both removing amyloid oligomers as well as inhibiting their formation. These data further support the use of semirational design combined with intracellular PCA methodology to develop A? antagonists as candidates for modification into drugs capable of slowing or even preventing the onset of AD.

Item Type: Article
DOI/Identification number: 10.1002/pro.2509
Subjects: Q Science
Divisions: Faculties > Sciences > School of Biosciences
Depositing User: N. Kad
Date Deposited: 15 Sep 2014 19:33 UTC
Last Modified: 06 May 2020 03:10 UTC
Resource URI: https://kar.kent.ac.uk/id/eprint/42936 (The current URI for this page, for reference purposes)
Kad, Neil M: https://orcid.org/0000-0002-3491-8595
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