Intracellular screening of a peptide library to derive a potent peptide inhibitor of α-synuclein aggregation.
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.
['Cheruvara|Harish|H|', 'Allen-Baume|Victoria L|VL|', 'Kad|Neil M|NM|', 'Mason|Jody M|JM|']
D000544:Alzheimer Disease D000595:Amino Acid Sequence D001483:Base Sequence D002942:Circular Dichroism D017931:DNA Primers D016631:Lewy Bodies D018625:Microscopy, Atomic Force D010300:Parkinson Disease D019151:Peptide Library D010455:Peptides D016133:Polymerase Chain Reaction D051844:alpha-Synuclein
Parkinson Disease Alpha-synuclein (α-Synuclein) Amyloid Library Screening Protein Misfolding Protein-Fragment Complementation Assay Protein-Protein Interaction