title: Development of an in-vivo active reversible butyrylcholinesterase inhibitor.
abstract: Alzheimer's disease (AD) is characterized by severe basal forebrain cholinergic deficit, which results in progressive and chronic deterioration of memory and cognitive functions. Similar to acetylcholinesterase, butyrylcholinesterase (BChE) contributes to the termination of cholinergic neurotransmission. Its enzymatic activity increases with the disease progression, thus classifying BChE as a viable therapeutic target in advanced AD. Potent, selective and reversible human BChE inhibitors were developed. The solved crystal structure of human BChE in complex with the most potent inhibitor reveals its binding mode and provides the molecular basis of its low nanomolar potency. Additionally, this compound is noncytotoxic and has neuroprotective properties. Furthermore, this inhibitor moderately crosses the blood-brain barrier and improves memory, cognitive functions and learning abilities of mice in a model of the cholinergic deficit that characterizes AD, without producing acute cholinergic adverse effects. Our study provides an advanced lead compound for developing drugs for alleviating symptoms caused by cholinergic hypofunction in advanced AD.
authors.affiliation: Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000 Ljubljana, Slovenia.
authors.forename: Urban
authors.initials: U
authors.lastname: Košak
authors.affiliation: Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000 Ljubljana, Slovenia.
authors.forename: Boris
authors.initials: B
authors.lastname: Brus
authors.affiliation: Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000 Ljubljana, Slovenia.
authors.forename: Damijan
authors.initials: D
authors.lastname: Knez
authors.affiliation: Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000 Ljubljana, Slovenia.
authors.forename: Roman
authors.initials: R
authors.lastname: Šink
authors.affiliation: Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000 Ljubljana, Slovenia.
authors.forename: Simon
authors.initials: S
authors.lastname: Žakelj
authors.affiliation: Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000 Ljubljana, Slovenia.
authors.forename: Jurij
authors.initials: J
authors.lastname: Trontelj
authors.affiliation: Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000 Ljubljana, Slovenia.
authors.forename: Anja
authors.initials: A
authors.lastname: Pišlar
authors.affiliation: Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000 Ljubljana, Slovenia.
authors.forename: Jasna
authors.initials: J
authors.lastname: Šlenc
authors.affiliation: Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000 Ljubljana, Slovenia.
authors.forename: Martina
authors.initials: M
authors.lastname: Gobec
authors.affiliation: Institute of Pathological Physiology, Faculty of Medicine, University of Ljubljana, Vrazov trg 2, 1000 Ljubljana, Slovenia.
authors.forename: Marko
authors.initials: M
authors.lastname: Živin
authors.affiliation: Institute of Pathological Physiology, Faculty of Medicine, University of Ljubljana, Vrazov trg 2, 1000 Ljubljana, Slovenia.
authors.forename: Larisa
authors.initials: L
authors.lastname: Tratnjek
authors.affiliation: Institute of Pathology, Faculty of Medicine, University of Ljubljana, Korytkova 2, 1000 Ljubljana, Slovenia.
authors.forename: Martina
authors.initials: M
authors.lastname: Perše
authors.affiliation: Faculty of Pharmacy, Jagiellonian University, Medyczna 9 St., 30-688 Krakow, Poland.
authors.forename: Kinga
authors.initials: K
authors.lastname: Sałat
authors.affiliation: Faculty of Pharmacy, Jagiellonian University, Medyczna 9 St., 30-688 Krakow, Poland.
authors.forename: Adrian
authors.initials: A
authors.lastname: Podkowa
authors.affiliation: Faculty of Pharmacy, Jagiellonian University, Medyczna 9 St., 30-688 Krakow, Poland.
authors.forename: Barbara
authors.initials: B
authors.lastname: Filipek
authors.affiliation: Institut de Recherche Biomédicale des Armées, 91223 Brétigny sur Orge, France.
authors.forename: Florian
authors.initials: F
authors.lastname: Nachon
authors.affiliation: Institut de Recherche Biomédicale des Armées, 91223 Brétigny sur Orge, France.
authors.forename: Xavier
authors.initials: X
authors.lastname: Brazzolotto
authors.affiliation: Faculty of Pharmacy, Jagiellonian University, Medyczna 9 St., 30-688 Krakow, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Więckowska
authors.affiliation: Faculty of Pharmacy, Jagiellonian University, Medyczna 9 St., 30-688 Krakow, Poland.
authors.forename: Barbara
authors.initials: B
authors.lastname: Malawska
authors.affiliation: Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Vrazov trg 2, 1000 Ljubljana, Slovenia.
authors.forename: Jure
authors.initials: J
authors.lastname: Stojan
authors.affiliation: Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000 Ljubljana, Slovenia.
authors.forename: Irena Mlinarič
authors.initials: IM
authors.lastname: Raščan
authors.affiliation: Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000 Ljubljana, Slovenia.
authors.forename: Janko
authors.initials: J
authors.lastname: Kos
authors.affiliation: University Grenoble Alpes, IBS, F-38044 Grenoble, France.|CNRS, IBS, F-38044 Grenoble, France.|CEA, IBS, F-38044 Grenoble, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Coquelle
authors.affiliation: University Grenoble Alpes, IBS, F-38044 Grenoble, France.|CNRS, IBS, F-38044 Grenoble, France.|CEA, IBS, F-38044 Grenoble, France.
authors.forename: Jacques-Philippe
authors.initials: JP
authors.lastname: Colletier
authors.affiliation: Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000 Ljubljana, Slovenia.
authors.forename: Stanislav
authors.initials: S
authors.lastname: Gobec
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy*; D000818:Animals; D001812:Blood-Brain Barrier; D001921:Brain / Q000473:pathology; D002091:Butyrylcholinesterase; D020134:Catalytic Domain; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D018450:Disease Progression; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D005260:Female; D006801:Humans; D007858:Learning; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011487:Protein Conformation; D051381:Rats; D017208:Rats, Wistar
chemical_list: D002800:Cholinesterase Inhibitors; D002091:Butyrylcholinesterase