Abstract
Aggregation of α-synuclein (α-syn) into toxic fibrils is a pathogenic hallmark of Parkinson's disease (PD). Studies have largely focused on residues 71-82, yet most early onset mutations are located between residues 46-53. A semi-rationally designed 209,952 member library 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 1:1 stoichiometry. This was verified using continuous growth measurements, and MTT 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 semi-rational design and intracellular screening. These peptides are candidates for modification into drugs capable of slowing or even preventing the onset of PD.
Original language | English |
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Pages (from-to) | 7426-7435 |
Number of pages | 10 |
Journal | Journal of Biological Chemistry |
Volume | 290 |
Issue number | 12 |
Early online date | 23 Jan 2015 |
DOIs | |
Publication status | Published - 20 Mar 2015 |