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.

Keywords:

• Multifunctional ligands
• β-secretase
• 5-HT6 receptor antagonists
• cholinesterase inhibitors

Disclosure statement

No potential conflict of interest was by reported the author(s).

Additional information

Funding

This study received financial support from the National Science Centre Poland [Grant No. 2016/23/D/NZ7/01328].