Target identification of natural medicine with chemical proteomics approach: probe synthesis, target fishing and protein identification

Abstract

Natural products are an important source of new drugs for the treatment of various diseases. However, developing natural product-based new medicines through random moiety modification is a lengthy and costly process, due in part to the difficulties associated with comprehensively understanding the mechanism of action and the side effects. Identifying the protein targets of natural products is an effective strategy, but most medicines interact with multiple protein targets, which complicate this process. In recent years, an increasing number of researchers have begun to screen the target proteins of natural products with chemical proteomics approaches, which can provide a more comprehensive array of the protein targets of active small molecules in an unbiased manner. Typically, chemical proteomics experiments for target identification consist of two key steps: (1) chemical probe design and synthesis and (2) target fishing and identification. In recent decades, five different types of chemical proteomic probes and their respective target fishing methods have been developed to screen targets of molecules with different structures, and a variety of protein identification approaches have been invented. Presently, we will classify these chemical proteomics approaches, the application scopes and characteristics of the different types of chemical probes, the different protein identification methods, and the advantages and disadvantages of these strategies.

Fig. 1

a Comparison of activity-based probe profiling and compound-centric chemical proteomics. b General molecular structures of different types of chemical proteomics probes

Fig. 2

Workflow of target identification with immobilized probes of natural medicines. a Identification of FK506 protein targets with an immobilized FK506 probe. b Identification of trapoxin protein targets with K-trap. c Structures of other reported immobilized probes of natural medicines

Fig. 3

Schematic of target identification with activity-based probes of natural medicines. a Target identification of resveratrol with its activity-based probe. b Structures of some previously reported activity-based probes of natural medicines

Fig. 4

Schematic of target identification with click chemistry probes of natural medicines. a Structures of some reported click chemistry probes of natural medicines. b Identification of artemisinin protein targets with its click chemistry probe. c Identification of ferroptocide protein targets with its click chemistry probe

Fig. 5

Schematic of target identification with photoaffinity probes of natural medicines. a Cholesterol target identification with its photoaffinity probe. b Structures of some reported photoaffinity probes of natural medicines. The photoaffinity groups are indicated in red

Fig. 6

a Schematic of target identification of ATP, PEP and l-Phe with DARTS. b Workflow of target fishing and MS identification. c Workflow of chemical proteomics combined with protein microarray

Fig. 7

Schematic of protein identification with SILAC. a General workflow of chemical proteomics combined with SILAC. b Target identification of zerumbone through a chemical proteomics approach coupled with SILAC

Fig. 8

Schematic of protein identification with iTRAQ. a Workflow of chemical proteomics combined with iTRAQ. b Andrographolide target identification with chemical proteomics combined with iTRAQ