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)

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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.

Keywords:butyrylcholinesterase, inhibitor, probe, fluorescence
Work type:Article (dk_c)
Tipology:1.01 - Original Scientific Article
Organization:FFA - Faculty of Pharmacy
Number of pages:Str. 498-505
Numbering:Vol. 35, iss. 1
ISSN on article:1475-6366
DOI:10.1080/14756366.2019.1710502 This link opens in a new window
COBISS.SI-ID:4869233 This link opens in a new window
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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
COBISS.SI-ID:512255001 This link opens in a new window

Document is financed by a project

Funder:ARRS - Agencija za raziskovalno dejavnost Republike Slovenije (ARRS)
Project no.:P1-0208
Name:Farmacevtska kemija: načrtovanje, sinteza in vrednotenje učinkovin

Funder:ARRS - Agencija za raziskovalno dejavnost Republike Slovenije (ARRS)
Project no.:L1-8157
Name:Razvoj multifunkcionalnih učinkovin za zdravljenje Alzheimerjeve bolezni

Funder:ARRS - Agencija za raziskovalno dejavnost Republike Slovenije (ARRS)
Project no.:NC-0009
Name:Razvoj novih karbamatnih sond za holinesteraze

Funder:Drugi - Drug financer ali več financerjev
Funding Programme:French Ministry of Armed Forces
Project no.:

Funder:Drugi - Drug financer ali več financerjev
Funding Programme:Agence Nationale de la Recherche
Project no.:ANR-12-BS07-0008–01

Funder:Drugi - Drug financer ali več financerjev
Funding Programme:France Alzheimer Foundation
Project no.:FA-AAP-2013–65-101349


License:CC BY 4.0, Creative Commons Attribution 4.0 International
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

Keywords:patogeneza Alzheimerjeve bolezni, butiriliholinesteraza, zaviralci

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