Development of an in-vivo active reversible butyrylcholinesterase inhibitor

• DOI: 10.1038/srep39495
• Publication Date: 2016-12-21T10:19:30Z
• Authors: Urban Košak; Boris Brus; Damijan Knez; Roman Šink; Simon Žakelj; Jurij Trontelj; Anja Pišlar; Jasna Šlenc; Martina Gobec; Marko Živin; Larisa Tratnjek; Martina Perše; Kinga Sałat; Adrian Podkowa; Barbara Filipek; Florian Nachon; Xavier Brazzolotto; Anna Więckowska; Barbara Malawska; Jure Stojan; Irena Mlinarič Ra...; Janko Kos; Nicolas Coquelle; Jacques-Philippe ...; Stanislav Gobec
• Keywords: Male; 0301 basic medicine; 570; Protein Conformation; Drug Evaluation, Preclinical; 610; [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry; Article; Mice; 03 medical and health sciences; Alzheimer Disease; Catalytic Domain; Animals; Humans; Learning; Chromatography, High Pressure Liquid; Mice, Knockout; [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM]; Molecular Biology/Structural Biology [q-bio.BM]; Brain; Rats; 3. Good health; Mice, Inbred C57BL; Blood-Brain Barrier; Butyrylcholinesterase; Drug Design; Disease Progression; Female; Cholinesterase Inhibitors

AbstractAlzheimer’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.