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Target identification with quantitative activity based protein profiling (ABPP).

Xiao Chen1, Yin Kwan Wong2,3, Jigang Wang1,2,3,4

  • 1The State Key Laboratory of Pharmaceutical Biotechnology, College of Life Sciences, Nanjing University, Nanjing, P. R., China.

Proteomics
|October 11, 2016
PubMed
Summary
This summary is machine-generated.

Identifying protein targets for bioactive small molecules is key to understanding their function and side effects. Activity-based protein profiling (ABPP) combined with quantitative chemical proteomics offers a high-flux, accurate method for this crucial drug discovery task.

Keywords:
Activity-based protein profiling (ABPP)BiomedicineNatural productsQuantitative chemical proteomicsSmall moleculesTarget identification

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Area of Science:

  • Chemical biology
  • Proteomics
  • Drug discovery

Background:

  • Small bioactive molecules function via protein interactions, necessitating target identification for understanding mechanisms of action (MOA) and side effects.
  • While natural products were historically the source, synthetic and remodeled small molecules offer therapeutic potential but require further MOA and side effect elucidation.
  • The promiscuity of small molecules and proteome complexity demand high-flux, high-accuracy target identification methods.

Purpose of the Study:

  • To review advances in quantitative chemical proteomics for small molecule target identification.
  • To introduce the principles of activity-based protein profiling (ABPP).
  • To illustrate the application of ABPP coupled with quantitative chemical proteomics in detecting drug and natural product targets.

Main Methods:

  • Discusses affinity chromatography with mass spectrometry (MS) and its limitations.
  • Highlights quantitative chemical proteomics approaches: metabolic labeling, chemical labeling, and label-free methods.
  • Emphasizes the integration of these quantitative methods with Activity-Based Protein Profiling (ABPP).

Main Results:

  • Quantitative chemical proteomics, particularly when combined with ABPP, overcomes limitations of traditional methods like affinity chromatography.
  • These integrated approaches enable rapid and accurate identification of small molecule protein targets.
  • Examples demonstrate successful application in identifying targets for drugs and natural products.

Conclusions:

  • ABPP coupled with quantitative chemical proteomics represents a significant advancement in small molecule target identification.
  • This powerful combination accelerates the understanding of MOA and potential side effects, aiding drug development.
  • The reviewed methodologies provide a robust framework for exploring the therapeutic potential of diverse small molecules.