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

Background: Deposition of α-synuclein into Lewy bodies is considered the primary event in Parkinson disease. Results: A peptide selected via PCA library screening functions by inhibiting fibril formation. Conclusion: A semirational design combined with intracellular PCA is an effective methodology to develop α-synuclein aggregation antagonists. Significance: The technique can be applied to a number of diseases from Parkinson to Alzheimer. Aggregation of α-synuclein (α-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 α-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 α-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.

• Publication year

  2015

• Venue

  Journal of Biological Chemistry

• Publication date

  2015-01-23

• Fields of study

  Medicine, Chemistry

• Identifiers
  DOI 10.1074/jbc.M114.620484PMID 25616660PMCID PMC4367252
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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