Multidirectional in vitro and in cellulo studies as a tool for identification of multi-target-directed ligands aiming at symptoms and causes of Alzheimer’s disease

Autor: Natalia Szałaj, Justyna Godyń, Jakub Jończyk, Anna Pasieka, Dawid Panek, Tomasz Wichur, Krzysztof Więckowski, Paula Zaręba, Marek Bajda, Anja Pislar, Barbara Malawska, Raimon Sabate, Anna Więckowska
Jazyk: angličtina
Rok vydání: 2020
Předmět:
Zdroj: Journal of Enzyme Inhibition and Medicinal Chemistry, Vol 35, Iss 1, Pp 1944-1952 (2020)
Druh dokumentu: article
ISSN: 1475-6366
1475-6374
14756366
DOI: 10.1080/14756366.2020.1835882
Popis: Effective therapy of Alzheimer’s disease (AD) requires treatment with a combination of drugs that modulate various pathomechanisms contributing to the disease. In our research, we have focused on the development of multi-target-directed ligands – 5-HT6 receptor antagonists and cholinesterase inhibitors – with disease-modifying properties. We have performed extended in vitro (FRET assay) and in cellulo (Escherichia coli model of protein aggregation) studies on their β-secretase, tau, and amyloid β aggregation inhibitory activity. Within these multifunctional ligands, we have identified compound 17 with inhibitory potency against tau and amyloid β aggregation in in cellulo assay of 59% and 56% at 10 µM, respectively, hBACE IC50=4 µM, h5TH6 Ki=94 nM, hAChE IC50=26 nM, and eqBuChE IC50=5 nM. This study led to the development of multifunctional ligands with a broad range of biological activities crucial not only for the symptomatic but also for the disease-modifying treatment of AD.
Databáze: Directory of Open Access Journals
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