title: Drugs That Bind to α-Synuclein: Neuroprotective or Neurotoxic?
abstract: The misfolding of α-synuclein is a critical event in the death of dopaminergic neurons and the progression of Parkinson's disease. Drugs that bind to α-synuclein and form a loop structure between the N- and C-terminus tend to be neuroprotective, whereas others that cause a more compact structure tend to be neurotoxic. The binding of several natural products and other drugs that are involved in dopamine metabolism were investigated by nanopore analysis and isothermal titration calorimetry. The antinausea drugs, cinnarizine and metoclopramide, do not bind to α-synuclein, whereas amphetamine and the herbicides, paraquat and rotenone, bind tightly and cause α-synuclein to adopt a more compact conformation. The recreational drug, cocaine, binds to α-synuclein, whereas heroin and methadone do not. Metformin, which is prescribed for diabetes and is neuroprotective, binds well without causing α-synuclein to adopt a more compact conformation. Methylphenidate (ritalin) binds to sites in both the N- and C-terminus and causes α-synuclein to adopt a loop conformation. In contrast, amphetamine only binds to the N-terminus. Except for cinnarizine and metoclopramide, there is a good correlation between the mode of binding to α-synuclein and whether a drug is neuroprotective or neurotoxic.
authors.affiliation: Department of Biochemistry, University of Saskatchewan , 107 Wiggins Road, Saskatoon, Canada , S7N 0W0.
authors.forename: Joe
authors.initials: J
authors.lastname: Kakish
authors.affiliation: Department of Biochemistry, University of Saskatchewan , 107 Wiggins Road, Saskatoon, Canada , S7N 0W0.
authors.forename: Dongsoo
authors.initials: D
authors.lastname: Lee
authors.affiliation: Department of Biochemistry, University of Saskatchewan , 107 Wiggins Road, Saskatoon, Canada , S7N 0W0.
authors.forename: Jeremy S
authors.initials: JS
authors.lastname: Lee
mesh_terms: D000818:Animals; D006801:Humans; D008968:Molecular Conformation; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D020258:Neurotoxicity Syndromes / Q000188:drug therapy*; D010300:Parkinson Disease / Q000188:drug therapy* / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D051844:alpha-Synuclein / Q000187:drug effects / Q000378:metabolism*
chemical_list: D018696:Neuroprotective Agents; D051844:alpha-Synuclein
keywords: Parkinson’s disease; isothermal titration calorimetry; nanopore analysis; neuroprotective drugs; neurotoxic drugs; protein folding; α-synuclein