Gobec M

References (2)

Title : Intracellular Hydrolysis of Small-Molecule O-Linked N-Acetylglucosamine Transferase Inhibitors Differs among Cells and Is Not Required for Its Inhibition - Loi_2020_Molecules_25_
Author(s) : Loi EM , Weiss M , Pajk S , Gobec M , Tomai T , Pieters RJ , Anderluh M
Ref : Molecules , 25 : , 2020
Abstract : O-GlcNAcylation is an essential post-translational modification that occurs on nuclear and cytoplasmic proteins, regulating their function in response to cellular stress and altered nutrient availability. O-GlcNAc transferase (OGT) is the enzyme that catalyzes this reaction and represents a potential therapeutic target, whose biological role is still not fully understood. To support this research field, a series of cell-permeable, low-nanomolar OGT inhibitors were recently reported. In this study, we resynthesized the most potent OGT inhibitor of the library, OSMI-4, and we used it to investigate OGT inhibition in different human cell lines. The compound features an ethyl ester moiety that is supposed to be cleaved by carboxylesterases to generate its active metabolite. Our LC-HRMS analysis of the cell lysates shows that this is not always the case and that, even in the cell lines where hydrolysis does not occur, OGT activity is inhibited.
ESTHER : Loi_2020_Molecules_25_
PubMedSearch : Loi_2020_Molecules_25_
PubMedID: 32722493

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