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Advanced Science

Advanced Science

IF: 14.3
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Degradation‐Based Protein Profiling: A Case Study of Celastrol

Published:25 April 2024 DOI: 10.1002/advs.202308186
Zhihao Ni, Yi Shi, Qianlong Liu, Liguo Wang, Xiuyun Sun, Yu Rao

Abstract

Natural products, while valuable for drug discovery, encounter limitations like uncertainty in targets and toxicity. As an important active ingredient in traditional Chinese medicine, celastrol exhibits a wide range of biological activities, yet its mechanism remains unclear. In this study, they introduced an innovative “Degradation-based protein profiling (DBPP)” strategy, which combined PROteolysis TArgeting Chimeras (PROTAC) technology with quantitative proteomics and Immunoprecipitation-Mass Spectrometry (IP-MS) techniques, to identify multiple targets of natural products using a toolbox of degraders. Taking celastrol as an example, they successfully identified its known targets, including inhibitor of nuclear factor kappa B kinase subunit beta (IKKβ), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PI3Kα), and cellular inhibitor of PP2A (CIP2A), as well as potential new targets such as checkpoint kinase 1 (CHK1), O-GlcNAcase (OGA), and DNA excision repair protein ERCC-6-like (ERCC6L). Furthermore, the first glycosidase degrader is developed in this work. Finally, by employing a mixed PROTAC toolbox in quantitative proteomics, they also achieved multi-target identification of celastrol, significantly reducing costs while improving efficiency. Taken together, they believe that the DBPP strategy can complement existing target identification strategies, thereby facilitating the rapid advancement of the pharmaceutical field.

Substances (4)

Materials
Procduct Name CAS Molecular Formula Supplier Price
MG-132 133407-82-6 C26H41N3O5 426 suppliers $11.00-$3568.00
MG-132 133407-82-6 C26H41N3O5 426 suppliers $11.00-$3568.00
MG-132 133407-82-6 C26H41N3O5 426 suppliers $11.00-$3568.00
MG-132 133407-82-6 C26H41N3O5 426 suppliers $11.00-$3568.00

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