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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.


ABSTRACT: 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 K i=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.

SUBMITTER: Szalaj N 

PROVIDER: S-EPMC7594877 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Multidirectional <i>in vitro</i> and <i>in cellulo</i> studies as a tool for identification of multi-target-directed ligands aiming at symptoms and causes of Alzheimer's disease.

Szałaj Natalia N   Godyń Justyna J   Jończyk Jakub J   Pasieka Anna A   Panek Dawid D   Wichur Tomasz T   Więckowski Krzysztof K   Zaręba Paula P   Bajda Marek M   Pislar Anja A   Malawska Barbara B   Sabate Raimon R   Więckowska Anna A  

Journal of enzyme inhibition and medicinal chemistry 20201201 1


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-HT<sub>6</sub> receptor antagonists and cholinesterase inhibitors - with disease-modifying properties. We have performed extended <i>in vitro</i> (FRET assay) and <i>in cellulo</i> (<i>Escherichia coli</i> model of protein aggregation) studies on thei  ...[more]

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