Development of potent reversible selective inhibitors of butyrylcholinesterase as fluorescent probes

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

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.

• Jezik: Angleški jezik
• Ključne besede: butyrylcholinesterase, inhibitor, probe, fluorescence
• Vrsta gradiva: Članek v reviji
• Tipologija: 1.01 - Izvirni znanstveni članek
• Organizacija: FFA - Fakulteta za farmacijo ; MF - Medicinska fakulteta
• Status publikacije: Objavljeno
• Različica publikacije: Objavljena publikacija
• Leto izida: 2020
• Št. strani: Str. 498-505
• Številčenje: Vol. 35, iss. 1
• PID: 20.500.12556/RUL-125368
• UDK: 616.894+616.892.3:615.2
• ISSN pri članku: 1475-6366
• DOI: 10.1080/14756366.2019.1710502
• COBISS.SI-ID: 4869233
• Datum objave v RUL: 12.03.2021

Gradivo je del revije

• Naslov: Journal of enzyme inhibition and medicinal chemistry
• Skrajšan naslov: J. enzyme inhib. med. chem.
• Založnik: Taylor & Francis
• ISSN: 1475-6366
• COBISS.SI-ID: 512255001

Licence

• Licenca: CC BY 4.0, Creative Commons Priznanje avtorstva 4.0 Mednarodna
• Povezava: http://creativecommons.org/licenses/by/4.0/deed.sl
• Opis: To je standardna licenca Creative Commons, ki daje uporabnikom največ možnosti za nadaljnjo uporabo dela, pri čemer morajo navesti avtorja.
• Začetek licenciranja: 12.03.2021

Sekundarni jezik

• Jezik: Slovenski jezik
• Ključne besede: patogeneza Alzheimerjeve bolezni, butiriliholinesteraza, zaviralci