Targeting the intrinsically disordered structural ensemble of α-synuclein by small molecules as a potential therapeutic strategy for Parkinson's disease

PLoS One. 2014 Feb 14;9(2):e87133. doi: 10.1371/journal.pone.0087133. eCollection 2014.

Abstract

The misfolding of intrinsically disordered proteins such as α-synuclein, tau and the Aβ peptide has been associated with many highly debilitating neurodegenerative syndromes including Parkinson's and Alzheimer's diseases. Therapeutic targeting of the monomeric state of such intrinsically disordered proteins by small molecules has, however, been a major challenge because of their heterogeneous conformational properties. We show here that a combination of computational and experimental techniques has led to the identification of a drug-like phenyl-sulfonamide compound (ELN484228), that targets α-synuclein, a key protein in Parkinson's disease. We found that this compound has substantial biological activity in cellular models of α-synuclein-mediated dysfunction, including rescue of α-synuclein-induced disruption of vesicle trafficking and dopaminergic neuronal loss and neurite retraction most likely by reducing the amount of α-synuclein targeted to sites of vesicle mobilization such as the synapse in neurons or the site of bead engulfment in microglial cells. These results indicate that targeting α-synuclein by small molecules represents a promising approach to the development of therapeutic treatments of Parkinson's disease and related conditions.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding Sites
  • Dopaminergic Neurons / drug effects
  • Dopaminergic Neurons / metabolism
  • Dopaminergic Neurons / pathology
  • Humans
  • Intrinsically Disordered Proteins / antagonists & inhibitors*
  • Intrinsically Disordered Proteins / chemistry
  • Intrinsically Disordered Proteins / metabolism
  • Mice
  • Models, Biological
  • Models, Molecular
  • Molecular Targeted Therapy*
  • Nerve Degeneration / metabolism
  • Nerve Degeneration / pathology
  • Parkinson Disease / drug therapy*
  • Parkinson Disease / pathology
  • Phagocytes / drug effects
  • Phagocytes / metabolism
  • Small Molecule Libraries / pharmacology*
  • Small Molecule Libraries / therapeutic use*
  • Synapses / drug effects
  • Synapses / metabolism
  • alpha-Synuclein / antagonists & inhibitors*
  • alpha-Synuclein / chemistry
  • alpha-Synuclein / metabolism

Substances

  • Intrinsically Disordered Proteins
  • Small Molecule Libraries
  • alpha-Synuclein