Entacapone and tolcapone, two catechol O-methyltransferase inhibitors, block fibril formation of alpha-synuclein and beta-amyloid and protect against amyloid-induced toxicity.
Parkinson disease (PD) is the second most common neurodegenerative disorder after Alzheimer disease (AD). There is considerable consensus that the increased production and/or aggregation of alpha-synuclein (alpha-syn) plays a central role in the pathogenesis of PD and related synucleinopathies. Current therapeutic strategies for treating PD offer mainly transient symptomatic relief and aim at the restitution of dopamine levels to counterbalance the loss of dopaminergic neurons. Therefore, the identification and development of drug-like molecules that block alpha-synuclein aggregation and prevent the loss of dopaminergic neurons are desperately needed to treat or slow the progression of PD. Here, we show that entacapone and tolcapone are potent inhibitors of alpha-syn and beta-amyloid (Abeta) oligomerization and fibrillogenesis, and they also protect against extracellular toxicity induced by the aggregation of both proteins. Comparison of the anti-aggregation properties of entacapone and tolcapone with the effect of five other catechol-containing compounds, dopamine, pyrogallol, gallic acid, caffeic acid, and quercetin on the oligomerization and fibrillization of alpha-syn and Abeta, demonstrate that the catechol moiety is essential for the anti-amyloidogenic activity. Our findings present the first characterization of the anti-amyloidogenic properties of tolcapone and entacapone against both alpha-synuclein and Abeta42 and highlight the potential of this class of nitro-catechol compounds as anti-amyloidogenic agents. Their inhibitory properties, mode of action, and structural properties suggest that they constitute promising lead compounds for further optimization.
Laboratory of Molecular Neurobiology and Neuroproteomics, Swiss Federal Institute of Technology Lausanne, SV-BMI-LMNN-AI2351, CH-1015 Lausanne, Switzerland.
Saviana
S
Di Giovanni
Laboratory of Molecular Neurobiology and Neuroproteomics, Swiss Federal Institute of Technology Lausanne, SV-BMI-LMNN-AI2351, CH-1015 Lausanne, Switzerland; Dipartimento di Biologia Evoluzionistica Sperimentale, Università di Bologna Via Selmi, 3, 40126 Bologna, Italy.
Simona
S
Eleuteri
Laboratory of Molecular Neurobiology and Neuroproteomics, Swiss Federal Institute of Technology Lausanne, SV-BMI-LMNN-AI2351, CH-1015 Lausanne, Switzerland.
Katerina E
KE
Paleologou
Max-Planck Institute for Biophysical Chemistry, NMR-based Structural Biology, Am Fassberg 11, 37077 Goettingen, Germany.
Guowei
G
Yin
Max-Planck Institute for Biophysical Chemistry, NMR-based Structural Biology, Am Fassberg 11, 37077 Goettingen, Germany; Deutsche Forschungsgemeinschaft Research Center for the Molecular Physiology of the Brain, Göttingen, Germany.
Markus
M
Zweckstetter
School of Pharmaceutical Sciences, University of Geneva and University of Lausanne, Quai Ernest-Ansermet 30, CH-1211, Genève 4, Switzerland.
Pierre-Alain
PA
Carrupt
Laboratory of Molecular Neurobiology and Neuroproteomics, Swiss Federal Institute of Technology Lausanne, SV-BMI-LMNN-AI2351, CH-1015 Lausanne, Switzerland. Electronic address: hilal.lashuel@epfl.ch.
Hilal A
HA
Lashuel
D016229:Amyloid beta-Peptides / Q000096:biosynthesis* / Q000633:toxicity; D000818:Animals; D001577:Benzophenones / Q000494:pharmacology*; D065098:Catechol O-Methyltransferase Inhibitors; D002396:Catechols / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D008854:Microscopy, Electron; D009570:Nitriles / Q000494:pharmacology*; D009596:Nitrophenols / Q000494:pharmacology*; D019906:Nuclear Magnetic Resonance, Biomolecular; D016716:PC12 Cells; D010446:Peptide Fragments / Q000096:biosynthesis* / Q000633:toxicity; D051381:Rats; D000077867:Tolcapone; D051844:alpha-Synuclein / Q000096:biosynthesis*
D016229:Amyloid beta-Peptides; D001577:Benzophenones; D065098:Catechol O-Methyltransferase Inhibitors; D002396:Catechols; D004791:Enzyme Inhibitors; D009570:Nitriles; D009596:Nitrophenols; D010446:Peptide Fragments; D051844:alpha-Synuclein; C075222:amyloid beta-protein (1-42); C071192:entacapone; D000077867:Tolcapone