Development of potent reversible selective inhibitors of butyrylcholinesterase as fluorescent probes

Pajk, Stane (author), Knez, Damijan (author), Košak, Urban (author), Zorović, Maja (author), Brazzolotto, Xavier (author), Coquelle, Nicolas (author), Nachon, Florian (author), Colletier, Jacques-Philippe (author), Živin, Marko (author), Stojan, Jure (author), Gobec, Stanislav (author)

Brain butyrylcholinesterase (BChE) is an attractive target for drugs designed for the treatment of Alzheimer's disease (AD) in its advanced stages. It also potentially represents a biomarker for progression of this disease. Based on the crystal structure of previously described highly potent, reversible, and selective BChE inhibitors, we have developed the fluorescent probes that are selective towards human BChE. The most promising probes also maintain their inhibition of BChE in the low nanomolar range with high selectivity over acetylcholinesterase. Kinetic studies of probes reveal a reversible mixed inhibition mechanism, with binding of these fluorescent probes to both the free and acylated enzyme. Probes show environment-sensitive emission, and additionally, one of them also shows significant enhancement of fluorescence intensity upon binding to the active site of BChE. Finally, the crystal structures of probes in complex with human BChE are reported, which offer an excellent base for further development of this library of compounds.

• Language: English
• Keywords: butyrylcholinesterase, inhibitor, probe, fluorescence
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: FFA - Faculty of Pharmacy; MF - Faculty of Medicine
• Publication status: Published
• Publication version: Version of Record
• Year: 2020
• Number of pages: Str. 498-505
• Numbering: Vol. 35, iss. 1
• PID: 20.500.12556/RUL-125368
• UDC: 616.894+616.892.3:615.2
• ISSN on article: 1475-6366
• DOI: 10.1080/14756366.2019.1710502
• COBISS.SI-ID: 4869233
• Publication date in RUL: 12.03.2021

Record is a part of a journal

• Title: Journal of enzyme inhibition and medicinal chemistry
• Shortened title: J. enzyme inhib. med. chem.
• Publisher: Taylor & Francis
• ISSN: 1475-6366
• COBISS.SI-ID: 512255001

Licences

• License: CC BY 4.0, Creative Commons Attribution 4.0 International
• Link: http://creativecommons.org/licenses/by/4.0/
• Description: This is the standard Creative Commons license that gives others maximum freedom to do what they want with the work as long as they credit the author.
• Licensing start date: 12.03.2021

Secondary language

• Language: Slovenian
• Keywords: patogeneza Alzheimerjeve bolezni, butiriliholinesteraza, zaviralci