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Multiplexed Thiol Reactivity Profiling for Target Discovery of Electrophilic Natural Products.
- Source :
-
Cell chemical biology [Cell Chem Biol] 2017 Nov 16; Vol. 24 (11), pp. 1416-1427.e5. Date of Electronic Publication: 2017 Oct 05. - Publication Year :
- 2017
-
Abstract
- Electrophilic groups, such as Michael acceptors, expoxides, are common motifs in natural products (NPs). Electrophilic NPs can act through covalent modification of cysteinyl thiols on functional proteins, and exhibit potent cytotoxicity and anti-inflammatory/cancer activities. Here we describe a new chemoproteomic strategy, termed multiplexed thiol reactivity profiling (MTRP), and its use in target discovery of electrophilic NPs. We demonstrate the utility of MTRP by identifying cellular targets of gambogic acid, an electrophilic NP that is currently under evaluation in clinical trials as anticancer agent. Moreover, MTRP enables simultaneous comparison of seven structurally diversified α,β-unsaturated γ-lactones, which provides insights into the relative proteomic reactivity and target preference of diverse structural scaffolds coupled to a common electrophilic motif and reveals various potential druggable targets with liganded cysteines. We anticipate that this new method for thiol reactivity profiling in a multiplexed manner will find broad application in redox biology and drug discovery.<br /> (Copyright © 2017 Elsevier Ltd. All rights reserved.)
- Subjects :
- Cell Line, Tumor
Chaperonin 60 antagonists & inhibitors
Chaperonin 60 metabolism
Chromatography, High Pressure Liquid
Cysteine chemistry
Humans
Lactones chemistry
Lactones metabolism
Tandem Mass Spectrometry
Xanthones chemistry
Xanthones metabolism
Biological Products chemistry
Sulfhydryl Compounds chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 2451-9448
- Volume :
- 24
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Cell chemical biology
- Publication Type :
- Academic Journal
- Accession number :
- 28988947
- Full Text :
- https://doi.org/10.1016/j.chembiol.2017.08.022