Trontelj J

References (3)

Title : Treatment of canine cognitive dysfunction with novel butyrylcholinesterase inhibitor - Zakosek Pipan_2021_Sci.Rep_11_18098
Author(s) : Zakosek Pipan M , Prpar Mihevc S , Strbenc M , Kosak U , German Ilic I , Trontelj J , Zakelj S , Gobec S , Pavlin D , Majdic G
Ref : Sci Rep , 11 :18098 , 2021
Abstract : Canine cognitive dysfunction (CCD) is common in aged dogs and has many similarities with Alzheimer's disease. Unfortunately, like Alzheimer's disease, CCD cannot be cured. In the present study, we treated dogs with CCD with our newly developed and characterized butyrylcholinesterase inhibitor (BChEi). Seventeen dogs were randomized into two groups (treated with BChEi and untreated) and followed for 6 months at regular check-ups. The dogs' cognitive status was determined by a Canine Dementia Scale (CADES) questionnaire and two cognitive tests. In dogs with moderate cognitive impairment, treatment caused significant improvement in the clinical rating of cognitive abilities and the performance-based tests of cognitive functioning when compared to the untreated group (p < 0.001). Dogs treated with BChEi showed markedly improved cognitive function with enhanced quality of life. No side effects were observed in the treated dogs with moderate cognitive impairment. According to the results of this preliminary study, there is an indication that novel BChEi may be a promising drug for the treatment of CCD in dogs and may be an interesting candidate for the treatment of Alzheimer's disease in humans. However, further clinical studies are needed to confirm this.
ESTHER : Zakosek Pipan_2021_Sci.Rep_11_18098
PubMedSearch : Zakosek Pipan_2021_Sci.Rep_11_18098
PubMedID: 34518582

Title : The Magic of Crystal Structure-Based Inhibitor Optimization: Development of a Butyrylcholinesterase Inhibitor with Picomolar Affinity and in Vivo Activity - Kosak_2018_J.Med.Chem_61_119
Author(s) : Kosak U , Brus B , Knez D , Zakelj S , Trontelj J , Pislar A , Sink R , Jukic M , Zivin M , Podkowa A , Nachon F , Brazzolotto X , Stojan J , Kos J , Coquelle N , Salat K , Colletier JP , Gobec S
Ref : Journal of Medicinal Chemistry , 61 :119 , 2018
Abstract : The enzymatic activity of butyrylcholinesterase (BChE) in the brain increases with the progression of Alzheimer's disease, thus classifying BChE as a promising drug target in advanced Alzheimer's disease. We used structure-based drug discovery approaches to develop potent, selective, and reversible human BChE inhibitors. The most potent, compound 3, had a picomolar inhibition constant versus BChE due to strong cation-pi interactions, as revealed by the solved crystal structure of its complex with human BChE. Additionally, compound 3 inhibits BChE ex vivo and is noncytotoxic. In vitro pharmacokinetic experiments show that compound 3 is highly protein bound, highly permeable, and metabolically stable. Finally, compound 3 crosses the blood-brain barrier, and it improves memory, cognitive functions, and learning abilities of mice in a scopolamine model of dementia. Compound 3 is thus a promising advanced lead compound for the development of drugs for alleviating symptoms of cholinergic hypofunction in patients with advanced Alzheimer's disease.
ESTHER : Kosak_2018_J.Med.Chem_61_119
PubMedSearch : Kosak_2018_J.Med.Chem_61_119
PubMedID: 29227101
Gene_locus related to this paper: human-BCHE

Title : Development of an in-vivo active reversible butyrylcholinesterase inhibitor - Kosak_2016_Sci.Rep_6_39495
Author(s) : Kosak U , Brus B , Knez D , Sink R , Zakelj S , Trontelj J , Pislar A , Slenc J , Gobec M , Zivin M , Tratnjek L , Perse M , Salat K , Podkowa A , Filipek B , Nachon F , Brazzolotto X , Wieckowska A , Malawska B , Stojan J , Rascan IM , Kos J , Coquelle N , Colletier JP , Gobec S
Ref : Sci Rep , 6 :39495 , 2016
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.
ESTHER : Kosak_2016_Sci.Rep_6_39495
PubMedSearch : Kosak_2016_Sci.Rep_6_39495
PubMedID: 28000737
Gene_locus related to this paper: human-BCHE