Avtor/Urednik		Szałaj, Natalia; Godyń, Justyna; Jończyk, Jakub; Pasieka, Anna; Panek, Dawid; Wichur, Tomasz; Więckowski, Krzysztof; Zaręba, Paula; Bajda, Marek; Pišlar, Anja; Malawska, Barbara; Sabaté, Raimon; Więckowska, Anna
Naslov		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
Tip		članek
Vol. in št.		Letnik 35, št. 1
Leto izdaje		2020
Obseg		str. 1944-1952
ISSN		1475-6374 - Journal of enzyme inhibition and medicinal chemistry
Jezik		eng
Abstrakt		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 [beta]-secretase, tau, and amyloid - aggregation inhibitory activity. Within these multifunctional ligands, we have identified compound 17 with inhibitory potency against tau and amyloid - aggregation in in cellulo assay of 59% and 56% at 10 [micro]M, respectively, hBACE IC50=4 [micro]M, 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.
Deskriptorji		Alzheimerjeva bolezen
Proste vsebinske oznake		multifunctional ligands [beta]-secretase 5-HT6 receptor antagonists cholinesterase inhibitors zaviralec holinesteraz človeški BACE1