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Proteomic characterization of post-translational modifications in drug discovery

Abstract

Protein post-translational modifications (PTMs), which are usually enzymatically catalyzed, are major regulators of protein activity and involved in almost all celluar processes. Dysregulation of PTMs is associated with various types of diseases. Therefore, PTM regulatory enzymes represent as an attractive and important class of targets in drug research and development. Inhibitors against kinases, methyltransferases, deacetyltransferases, ubiquitin ligases have achieved remarkable success in clinical application. Mass spectrometry-based proteomics technologies serve as a powerful approach for system-wide characterization of PTMs, which facilitates the identification of drug targets, elucidation of the mechanisms of action of drugs, and discovery of biomakers in personalized therapy. In this review, we summarize recent advances of proteomics-based studies on PTM targeting drugs and discuss how proteomics strategies facilicate drug target identification, mechanism elucidation, and new therapy development in precision medicine.

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Fig. 1: Different mass-spectrometry-based proteomic technologies in drug research.
Fig. 2: Schematic diagram of proteomics strategies in study on drugs targeting phosphorylaton.
Fig. 3: Schematic diagram of proteomics strategies in studying drugs targeting acetylation and methylation.
Fig. 4: Proteomics strategies to explore protein turnover, E3 ligase complex dynamics and degraded substrates regulated by drugs targeting ubiquitin-proteasome system.

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Acknowledgements

This work was supported by grants from the Basic research projects of Shanghai Science and Technology Commission “science and technology innovation action plan” (No. 19JC1416300), the National Natural Science Foundation of China (No. 32071432; No. 32171434), the Youth Science and Technology Talents in Shanghai Sail Plan of China (No. 21YF1456000), the State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, China (Grant No. KF-202201), the Innovative Research Team of High-Level Local Universities in Shanghai (SHSMU-ZDCX20212700), the Guangdong High-level new R&D institute (2019B090904008), the Guangdong High-level Innovative Research Institute (2021B0909050003), the Program of Shanghai Academic Research Leader (22XD1420900).

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Zhai, Lh., Chen, Kf., Hao, Bb. et al. Proteomic characterization of post-translational modifications in drug discovery. Acta Pharmacol Sin 43, 3112–3129 (2022). https://doi.org/10.1038/s41401-022-01017-y

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Keywords

  • proteomics
  • protein post-translational modification
  • drug target
  • off-target
  • drug mechanism
  • precision medicine

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