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

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.
Gergely Tóth 1,  Shyra J Gardai 2,  Wagner Zago 2,  Carlos W Bertoncini 3,  Nunilo Cremades 4,  Susan L Roy 5,  Mitali A Tambe 5,  Jean-Christophe Rochet 5,  Celine Galvagnion 4,  Gaia Skibinski 6,  Steven Finkbeiner 7,  Michael Bova 2,  Karin Regnstrom 2,  San-San Chiou 2,  Jennifer Johnston 2,  Kari Callaway 2,  John P Anderson 2,  Michael F Jobling 2,  Alexander K Buell 4,  Ted A Yednock 2,  Tuomas P J Knowles 4,  Michele Vendruscolo 4,  John Christodoulou 8,  Christopher M Dobson 4,  Dale Schenk 2,  Lisa McConlogue 2
Affiliations

Affiliations

  • 1 Department of Chemistry, University of Cambridge, Cambridge, United Kingdom ; Elan Pharmaceuticals, South San Francisco, California, United States of America.
  • 2 Elan Pharmaceuticals, South San Francisco, California, United States of America.
  • 3 Department of Chemistry, University of Cambridge, Cambridge, United Kingdom ; SEDIPFAR (Servicio De Descubrimiento, Diseño Y Desarrollo Pre-Clínico De Fármacos De La Argentina) drug discovery platform, Universidad Nacional de Rosario, Rosario, Argentina.
  • 4 Department of Chemistry, University of Cambridge, Cambridge, United Kingdom.
  • 5 Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, Indiana, United States of America.
  • 6 Gladstone Institute of Neurological Disease, San Francisco, California, United States of America ; Taube-Koret Center for Neurodegenerative Disease Research, The Consortium for Frontotemporal Dementia Research, and The Hellman Family Foundation Program for Alzheimer's Disease Research, San Francisco, California, United States of America.
  • 7 Gladstone Institute of Neurological Disease, San Francisco, California, United States of America ; Taube-Koret Center for Neurodegenerative Disease Research, The Consortium for Frontotemporal Dementia Research, and The Hellman Family Foundation Program for Alzheimer's Disease Research, San Francisco, California, United States of America ; Departments of Neurology and Physiology, UCSF, San Francisco, California, United States of America.
  • 8 Department of Structural & Molecular Biology, University College London, London, United Kingdom.
PMID: 24551051 DOI: 10.1371/journal.pone.0087133
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.

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