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Current Drug Targets

Author(s): Menghan Zhu, Dongxia Qi, Dongliang Chen, Wenchong Ye, Xiaoyang Wang, Chunmei Wang, Wen Zhou, Bin Zhou, Juan Li* and Keyu Zhang*

DOI: 10.2174/0113894501297697240805103744

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Joint Screening and Identification of Potential Targets of Nitazoxanide by Affinity Chromatography and Label-Free Techniques

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Abstract

Background: Nitazoxanide not only exhibits a broad spectrum of activities against various pathogens infecting animals and humans but also induces cellular autophagy. Currently, the pattern of action and subcellular targets of nitazoxanide-induced cellular autophagy are still unclear.

Methods: To identify potential targets of nitazoxanide in mammalian cells, we developed an affinity chromatography system using tizoxanide, a deacetyl derivative of nitazoxanide, as a ligand. Affinity chromatography was performed using VERO cell extracts on tizoxanide-biotin, and the isolated binding proteins were identified by mass spectrometry. Candidate target proteins obtained using affinity chromatography were co-analysed with the drug affinity response target stability method. Fluorescent probes obtained by coupling rhodamine B to nitazoxanide were used for intracellular localisation of the binding targets. Solvent-induced protein precipitation profiling and thermal proteome profiling were used to further validate the binding proteins.

Results: The joint analysis of the drug affinity response target stability method and affinity chromatography resulted in the screening of six possible candidate target proteins. Fluorescent probes localised the nitazoxanide-binding protein around the nuclear membrane. Molecular docking revealed that the binding proteins mainly formed hydrogen bonds with the nitro group of nitazoxanide. Solvent-induced protein precipitation profiling and thermal proteome profiling further validated SEC61A, PSMD12, and PRKAG1 as potential target proteins of nitazoxanide.

Conclusion: The data supports the idea that nitazoxanide is a multifunctional compound with multiple targets.

Keywords: Alzheimer's disease, atherosclerosis, nitazoxanide, affinity chromatography, drug target, autophagy.

Graphical Abstract

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