Abstract
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.
Highlights
Alzheimer’s disease (AD) is the most common form of senile dementia, and its prevalence is expected to increase further in the coming decades due to ageing of the populations in the Western world[1]
To save time in future studies by enabling easier substitution of the fluorophore moiety, we introduced a short linker with an azide into compound 3, which can react with any fluorophore that is functionalised by an alkyne group, according to “click chemistry” (copper(I)-catalyzed alkyne-azide cycloaddition)[38,39]
We report here on the design, synthesis, kinetics and spectroscopic characterisation and binding modes of the two potent BChE-specific fluorescent probes
Summary
Alzheimer’s disease (AD) is the most common form of senile dementia, and its prevalence is expected to increase further in the coming decades due to ageing of the populations in the Western world[1]. It includes accumulation of the amyloid b protein (Ab) and abnormal modifications and accumulation of the hyperphosphorylated protein tau, which is accompanied by oxidative stress. This leads to synaptic loss, selective neuronal death, and decreased brain concentrations of specific neurotransmitters, most notably of acetylcholine (ACh)[3]. The available treatments for AD include cholinesterase inhibitors and memantine, an N-methyl-D-aspartate (NMDA) receptor inhibitor These medications do not change the course of the disease nor the rate of patient decline, despite improving the quality of life for both patient and caregiver[5]
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