Development of an in-vivo active reversible butyrylcholinesterase inhibitor.
Urban Košak
(1)
,
Boris Brus
(1)
,
Damijan Knez
(1)
,
Roman Šink
(1)
,
Simon Žakelj
(1)
,
Jurij Trontelj
(1)
,
Anja Pišlar
(1)
,
Jasna Šlenc
(1)
,
Martina Gobec
(1)
,
Marko Živin
(2)
,
Larisa Tratnjek
(2)
,
Martina Perše
(3)
,
Kinga Sałat
(4)
,
Adrian Podkowa
(4)
,
Barbara Filipek
(4)
,
Florian Nachon
(5)
,
Xavier Brazzolotto
(5)
,
Anna Więckowska
(4)
,
Barbara Malawska
(4)
,
Jure Stojan
(6)
,
Irena Mlinarič Raščan
(1)
,
Janko Kos
(1)
,
Nicolas Coquelle
(7)
,
Jacques-Philippe Colletier
(7)
,
Stanislav Gobec
(1)
1
Faculty of Pharmacy
2 Institute of Pathological Physiology, Faculty of Medicine
3 Institute of Pathology, Faculty of Medicine
4 Faculty of Pharmacy
5 IRBA - Institut de Recherche Biomédicale des Armées [Brétigny-sur-Orge]
6 Institute of Biochemistry, Faculty of Medicine
7 IBS - UMR 5075 - Institut de biologie structurale
2 Institute of Pathological Physiology, Faculty of Medicine
3 Institute of Pathology, Faculty of Medicine
4 Faculty of Pharmacy
5 IRBA - Institut de Recherche Biomédicale des Armées [Brétigny-sur-Orge]
6 Institute of Biochemistry, Faculty of Medicine
7 IBS - UMR 5075 - Institut de biologie structurale
Florian Nachon
- Fonction : Auteur
- PersonId : 765718
- ORCID : 0000-0003-0293-2429
- IdRef : 138014787
Barbara Malawska
- Fonction : Auteur
- PersonId : 781075
- ORCID : 0000-0003-4637-5820
Jacques-Philippe Colletier
- Fonction : Auteur
- PersonId : 739662
- IdHAL : jacques-philippe-colletier
- ORCID : 0000-0003-1819-4686
- IdRef : 110264983
Résumé
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.