Drugs That Bind to α-Synuclein: Neuroprotective or Neurotoxic?
Identifieur interne : 000750 ( Main/Exploration ); précédent : 000749; suivant : 000751Drugs That Bind to α-Synuclein: Neuroprotective or Neurotoxic?
Auteurs : Joe Kakish ; Dongsoo Lee ; Jeremy S. LeeSource :
- ACS chemical neuroscience [ 1948-7193 ] ; 2015.
English descriptors
- KwdEn :
- MESH :
- chemical , drug effects : alpha-Synuclein.
- chemical , metabolism : alpha-Synuclein.
- chemical , therapeutic use : Neuroprotective Agents.
- drug effects : Protein Binding.
- drug therapy : Neurotoxicity Syndromes, Parkinson Disease.
- metabolism : Parkinson Disease.
- Animals, Humans, Molecular Conformation.
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.
DOI: 10.1021/acschemneuro.5b00172
PubMed: 26378986
Affiliations:
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Le document en format XML
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Lee</name><affiliation><nlm:affiliation>Department of Biochemistry, University of Saskatchewan , 107 Wiggins Road, Saskatoon, Canada , S7N 0W0.</nlm:affiliation><wicri:noCountry code="subField">S7N 0W0</wicri:noCountry></affiliation></author></analytic><series><title level="j">ACS chemical neuroscience</title><idno type="eISSN">1948-7193</idno><imprint><date when="2015" type="published">2015</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals</term><term>Humans</term><term>Molecular Conformation</term><term>Neuroprotective Agents (therapeutic use)</term><term>Neurotoxicity Syndromes (drug therapy)</term><term>Parkinson Disease (drug therapy)</term><term>Parkinson Disease (metabolism)</term><term>Protein Binding (drug effects)</term><term>alpha-Synuclein (drug effects)</term><term>alpha-Synuclein (metabolism)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="drug effects" xml:lang="en"><term>alpha-Synuclein</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>alpha-Synuclein</term></keywords><keywords scheme="MESH" type="chemical" qualifier="therapeutic use" xml:lang="en"><term>Neuroprotective Agents</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Protein Binding</term></keywords><keywords scheme="MESH" qualifier="drug therapy" xml:lang="en"><term>Neurotoxicity Syndromes</term><term>Parkinson Disease</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Parkinson Disease</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Humans</term><term>Molecular Conformation</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">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.</div></front></TEI><affiliations><list></list><tree><noCountry><name sortKey="Kakish, Joe" sort="Kakish, Joe" uniqKey="Kakish J" first="Joe" last="Kakish">Joe Kakish</name><name sortKey="Lee, Dongsoo" sort="Lee, Dongsoo" uniqKey="Lee D" first="Dongsoo" last="Lee">Dongsoo Lee</name><name sortKey="Lee, Jeremy S" sort="Lee, Jeremy S" uniqKey="Lee J" first="Jeremy S" last="Lee">Jeremy S. Lee</name></noCountry></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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