title: Application of BACE1 immobilized enzyme reactor for the characterization of multifunctional alkaloids from Corydalis cava (Fumariaceae) as Alzheimer's disease targets.
abstract: In our ongoing study focused on Corydalis cava (Fumariaceae), used in folk medicine in the treatment of memory dysfunctions, we have investigated fifteen previously isolated alkaloids for their potential multifunctional activity on Alzheimer's disease (AD) targets. Determination of ß-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibition was carried out using a BACE1-Immobilized Enzyme Reactor (IMER) by validating the assay with a multi-well plate format Fluorescence Resonance Energy Transfer (FRET) assay. Seven alkaloids out of fifteen were found to be active, with (-)-corycavamine (3) and (+)-corynoline (5) demonstrating the highest BACE1 inhibition activity, in the micromolar range, in a concentration dependent manner. BACE1-IMER was found to be a valid device for the fast screening of inhibitors and the determination of their potency. In a permeation assay (PAMPA) for the prediction of blood-brain barrier (BBB) penetration, the most active compounds, (-)-corycavamine (3) and (+)-corynoline (5), were found to be able to cross the BBB. Not all compounds showed activity against glycogen synthase kinase-3β (GSK-3β) and casein kinase-1δ (CK-1δ). On the basis of the reported results, we found that some C. cava alkaloids have multifunctional activity against AD targets (prolyl oligopeptidase, cholinesterases and BACE1). Moreover, we tried to elucidate the treatment effectivity (rational use) of its extract in memory dysfunction in folk medicine.
authors.affiliation: ADINACO Research Group, Department of Pharmaceutical Botany and Ecology, Faculty of Pharmacy, Charles University, Heyrovského 1203, 500 05 Hradec Králové, Czech Republic. Electronic address: jakub.chlebek@faf.cuni.cz.
authors.forename: Jakub
authors.initials: J
authors.lastname: Chlebek
authors.affiliation: Department for Life Quality Studies, Alma Mater Studiorum - University of Bologna, Corso d'Augusto 237, 47 921 Rimini, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: De Simone
authors.affiliation: ADINACO Research Group, Department of Pharmaceutical Botany and Ecology, Faculty of Pharmacy, Charles University, Heyrovského 1203, 500 05 Hradec Králové, Czech Republic.
authors.forename: Anna
authors.initials: A
authors.lastname: Hošťálková
authors.affiliation: ADINACO Research Group, Department of Pharmaceutical Botany and Ecology, Faculty of Pharmacy, Charles University, Heyrovského 1203, 500 05 Hradec Králové, Czech Republic.
authors.forename: Lubomír
authors.initials: L
authors.lastname: Opletal
authors.affiliation: Medicinal Chemistry Institute-CSIC, Juan de la Cierva 3, 280 06 Madrid, Spain.
authors.forename: Concepción
authors.initials: C
authors.lastname: Pérez
authors.affiliation: Centro de Investigaciones Biológicas (CIB-CSIC), Avenida Ramiro de Maetzu 9, 280 40 Madrid, Spain.
authors.forename: Daniel I
authors.initials: DI
authors.lastname: Pérez
authors.affiliation: Department of Analytical Chemistry, Faculty of Pharmacy, Charles University, Heyrovského 1203, 500 05 Hradec Králové, Czech Republic.
authors.forename: Lucie
authors.initials: L
authors.lastname: Havlíková
authors.affiliation: ADINACO Research Group, Department of Pharmaceutical Botany and Ecology, Faculty of Pharmacy, Charles University, Heyrovského 1203, 500 05 Hradec Králové, Czech Republic.
authors.forename: Lucie
authors.initials: L
authors.lastname: Cahlíková
authors.affiliation: Department for Life Quality Studies, Alma Mater Studiorum - University of Bologna, Corso d'Augusto 237, 47 921 Rimini, Italy.
authors.forename: Vincenza
authors.initials: V
authors.lastname: Andrisano
mesh_terms: D000470:Alkaloids / Q000737:chemistry* / Q000302:isolation & purification; D000544:Alzheimer Disease; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D001600:Berberine Alkaloids / Q000737:chemistry / Q000302:isolation & purification; D001812:Blood-Brain Barrier; D031311:Corydalis / Q000737:chemistry*; D004800:Enzymes, Immobilized / Q000037:antagonists & inhibitors*; D006801:Humans; D011994:Recombinant Proteins
chemical_list: D000470:Alkaloids; D001600:Berberine Alkaloids; D004800:Enzymes, Immobilized; D011994:Recombinant Proteins; C487644:corynoline; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; C000608998:corycavamine
keywords: Allocryptopine (PubChem CID: 98570); BACE1 inhibitors; Canadaline (PubChem CID: 321459); Canadine (PubChem CID: 443422); Corycavamine (PubChem CID: 90478581); Corycavidine (PubChem CID: 12304033); Corydalis cava alkaloids; Corynoline (PubChem CID: 177014); Corypalmine (PubChem CID: 12304090); Immobilized enzyme reactor; Isocorypalmine (PubChem CID: 10220); PAMPA assay; Scoulerine (PubChem CID: 22955)