Use Quantitative Chemical Proteomics Methods To Explore The Target Proteins Of Selenoline Drugs

Recent research on the use of chemical small molecule probes to explore drug target proteins has made great progress with the continuous development of chemical proteomics.Ebselen is capable of exerting mimicking enzymes in vivo due to their specific structure,and can be used for the prevention and treatment of various diseases.Ethaselen can interact with the active site of thioredoxin reductase,effectively inhibit the catalytic activity of thioredoxin reductase,affect the expression of key proteins regulating cell cycle,and thus inhibit tumor growth.Ebselen and ethaneselen have the same selenium-nitrogen bond structure,which can covalently modify a variety of proteins.However,the previous research on the proteins targeted by these two drugs is basically through the study of individual proteins or through the their derivatives to target proteins in vivo,which has led to slower research on selenium-based drug targeting proteins or the results cannot be more accurate.In response to the problems,we synthesized two small-molecule probes(Biotin-Ebselen and Alk-BBSKE)to investigate the proteins that can be covalently targeted by ebselen and ethaneselen in the proteome range.At the same time,quantitative chemical proteomics can identify target proteins of ebselen or ethaneselen in a certain cell or tissue with high throughput,high efficiency and more precise andthis will allow a more comprehensive analysis of the important role that selenium drugs can play in the body.The main work of this paper includes the following:1.Herein,based on a biotinylated ebselen probe(Biotin-Ebselen),we developed a highly efficient activity-based protein profiling(ABPP)method for ebselen-binding proteins.This method allowed for the robust identification of 462 targeted proteins,most of which have not been previously reported to be targeted by ebselen,including 15 core histone proteins,implicating multifunctional regulation of ebselen.The outcome will be helpful to re-design the ebselen-based therapy appropriately in clinical trials.2.In view of the current research on ethaneselen and its derivatives,mainly focusing on its role in thioredoxin and its anticancer effects on various cancer cells,the target protein research in its protein group has not been involved.Based on the specific selenium-nitrogen bond structure and the above studies on ebselen target proteins,we will use quantitative proteomics to explore the target proteins of ethaneselen.High-throughput identification of target proteins covalently interacting with ethaneselen was performed by chemical proteomics by designing alkyl selenium small molecule probe Alk-BBSKE with alkyne groups.These results will provide important information for the analysis of the efficacy of ethaneselen in clinical trials.