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Intracellular Screening of a Peptide Library to Derive a Potent Peptide Inhibitor of ?-Synuclein Aggregation

Cheruvara, Harish, Kad, Neil M, Mason, Jody M (2015) Intracellular Screening of a Peptide Library to Derive a Potent Peptide Inhibitor of ?-Synuclein Aggregation. Journal of Biological Chemistry, 290 (12). pp. 7426-7435. ISSN 0021-9258. (doi:10.1074/jbc.M114.620484) (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)

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/10.1074/jbc.M114.620484

Abstract

Aggregation of ?-synuclein (?-syn) into toxic fibrils is a pathogenic hallmark of Parkinson disease (PD). Studies have focused largely on residues 71-82, yet most early-onset mutations are located between residues 46 and 53. A semirationally designed 209,952-member library based entirely on this region was constructed, containing all wild-type residues and changes associated with early-onset PD. Intracellular cell survival screening and growth competition isolated a 10-residue peptide antagonist that potently inhibits ?-syn aggregation and associated toxicity at a 1:1 stoichiometry. This was verified using continuous growth measurements and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide cytotoxicity studies. Atomic force microscopy and circular dichroism on the same samples showed a random-coil structure and no oligomers. A new region of ?-syn for inhibitor targeting has been highlighted, together with the approach of using a semirational design and intracellular screening. The peptides can then be used as candidates for modification in drugs capable of slowing or even preventing the onset of PD.

Item Type: Article
DOI/Identification number: 10.1074/jbc.M114.620484
Uncontrolled keywords: Alpha-synuclein (?-Synuclein) Amyloid Parkinson Disease Protein Misfolding Protein-Protein Interaction Library Screening Protein-Fragment Complementation Assay
Subjects: Q Science > Q Science (General)
Divisions: Faculties > Sciences > School of Biosciences
Faculties > Sciences > School of Biosciences > Protein Science Group
Depositing User: N. Kad
Date Deposited: 29 Apr 2015 13:19 UTC
Last Modified: 29 May 2019 14:28 UTC
Resource URI: https://kar.kent.ac.uk/id/eprint/48115 (The current URI for this page, for reference purposes)
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