Using celastrol as a case study, this review summarizes various target discovery strategies for natural products, including chemical proteomics, protein microarray, degradation-based protein profiling, proteome-wide label-free approaches, network pharmacology, target-based drug screening, and indirect strategies. It emphasizes the critical importance of the target discovery platforms and identified target information in bioactivity discovery, mechanism of action clarification, toxicity assessment, combination therapy, drug delivery, and clinical application of celastrol.
Abstract:
Celastrol (CEL) is a natural pentacyclic triterpenoid demonstrating significant therapeutic properties against various diseases. However, the ambiguity of target information poses a significant challenge in transitioning CEL from a traditional remedy to a modern pharmaceutical agent. Recently, the emerging target discovery approaches of natural products have broadened extensive avenues for uncovering comprehensive target information of CEL and promoting its drug development. Herein, diverse target discovery strategies are overviewed for the pharmacological and toxicological studies of CEL, including chemical proteomics, protein microarray, degradation-based protein profiling, proteome-wide label-free approaches, network pharmacology, target-based drug screening, multi-omics analysis, and hypothesis-driven target confirmation. Dozens of CEL targets have been identified, which significantly suggests that CEL functions as a multi-target therapeutic agent. Further network interaction analysis and frequency analysis of collected targets reveal that PRDXs, HMGB1, HSP90, STAT3, and PKM2 may serve as key targets for CEL. Additionally, this review highlights the positive role of target discovery in facilitating CEL-based combination therapy and drug delivery, which is essential for further advancing the clinical applications of CEL. Efforts in CEL target identification not only aid in unraveling the scientific underpinnings of its multiple pharmacological effects but also offer crucial insights for further drug development of CEL-based drugs.
Author list:
Yanbei Tu†, Guiyu Dai†, Yanyan Chen, Lihua Tan, Hanqing Liu*, Meiwan Chen*
How to cite:
Y. Tu, G. Dai, Y. Chen, L. Tan, H. Liu, M. Chen, Exploration 2025, 20240247.
https://doi.org/10.1002/EXP.20240247