title: Targeting the intrinsically disordered structural ensemble of α-synuclein by small molecules as a potential therapeutic strategy for Parkinson's disease.
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.
authors.affiliation: Department of Chemistry, University of Cambridge, Cambridge, United Kingdom ; Elan Pharmaceuticals, South San Francisco, California, United States of America.
authors.forename: Gergely
authors.initials: G
authors.lastname: Tóth
authors.affiliation: Elan Pharmaceuticals, South San Francisco, California, United States of America.
authors.forename: Shyra J
authors.initials: SJ
authors.lastname: Gardai
authors.affiliation: Elan Pharmaceuticals, South San Francisco, California, United States of America.
authors.forename: Wagner
authors.initials: W
authors.lastname: Zago
authors.affiliation: 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.
authors.forename: Carlos W
authors.initials: CW
authors.lastname: Bertoncini
authors.affiliation: Department of Chemistry, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Nunilo
authors.initials: N
authors.lastname: Cremades
authors.affiliation: Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, Indiana, United States of America.
authors.forename: Susan L
authors.initials: SL
authors.lastname: Roy
authors.affiliation: Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, Indiana, United States of America.
authors.forename: Mitali A
authors.initials: MA
authors.lastname: Tambe
authors.affiliation: Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, Indiana, United States of America.
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Rochet
authors.affiliation: Department of Chemistry, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Celine
authors.initials: C
authors.lastname: Galvagnion
authors.affiliation: 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.
authors.forename: Gaia
authors.initials: G
authors.lastname: Skibinski
authors.affiliation: 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.
authors.forename: Steven
authors.initials: S
authors.lastname: Finkbeiner
authors.affiliation: Elan Pharmaceuticals, South San Francisco, California, United States of America.
authors.forename: Michael
authors.initials: M
authors.lastname: Bova
authors.affiliation: Elan Pharmaceuticals, South San Francisco, California, United States of America.
authors.forename: Karin
authors.initials: K
authors.lastname: Regnstrom
authors.affiliation: Elan Pharmaceuticals, South San Francisco, California, United States of America.
authors.forename: San-San
authors.initials: SS
authors.lastname: Chiou
authors.affiliation: Elan Pharmaceuticals, South San Francisco, California, United States of America.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Johnston
authors.affiliation: Elan Pharmaceuticals, South San Francisco, California, United States of America.
authors.forename: Kari
authors.initials: K
authors.lastname: Callaway
authors.affiliation: Elan Pharmaceuticals, South San Francisco, California, United States of America.
authors.forename: John P
authors.initials: JP
authors.lastname: Anderson
authors.affiliation: Elan Pharmaceuticals, South San Francisco, California, United States of America.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Jobling
authors.affiliation: Department of Chemistry, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Alexander K
authors.initials: AK
authors.lastname: Buell
authors.affiliation: Elan Pharmaceuticals, South San Francisco, California, United States of America.
authors.forename: Ted A
authors.initials: TA
authors.lastname: Yednock
authors.affiliation: Department of Chemistry, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Tuomas P J
authors.initials: TP
authors.lastname: Knowles
authors.affiliation: Department of Chemistry, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Michele
authors.initials: M
authors.lastname: Vendruscolo
authors.affiliation: Department of Structural & Molecular Biology, University College London, London, United Kingdom.
authors.forename: John
authors.initials: J
authors.lastname: Christodoulou
authors.affiliation: Department of Chemistry, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Dobson
authors.affiliation: Elan Pharmaceuticals, South San Francisco, California, United States of America.
authors.forename: Dale
authors.initials: D
authors.lastname: Schenk
authors.affiliation: Elan Pharmaceuticals, South San Francisco, California, United States of America.
authors.forename: Lisa
authors.initials: L
authors.lastname: McConlogue
mesh_terms: D000818:Animals; D001665:Binding Sites; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D064267:Intrinsically Disordered Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D008958:Models, Molecular; D058990:Molecular Targeted Therapy; D009410:Nerve Degeneration / Q000378:metabolism / Q000473:pathology; D010300:Parkinson Disease / Q000188:drug therapy* / Q000473:pathology; D010586:Phagocytes / Q000187:drug effects / Q000378:metabolism; D054852:Small Molecule Libraries / Q000494:pharmacology* / Q000627:therapeutic use*; D013569:Synapses / Q000187:drug effects / Q000378:metabolism; D051844:alpha-Synuclein / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism
chemical_list: D064267:Intrinsically Disordered Proteins; D054852:Small Molecule Libraries; D051844:alpha-Synuclein