Abstract

Natural product celastrol is known to have various biological activities, yet its molecular targets that correspond to many activities remain unclear1. Celastrol, a pentacyclic triterpene with electrophilic quinone methide extracted from Tripterygium wilfordii, was recognized as one of five promising natural products for drug discovery2. Here we synthesized chemical probes to mimic the natural product celastrol and identified catechol-O-methyltransferase (COMT) as its major binding target with comprehensive chemical proteomics approaches3. The covalent irreversible interaction between celastrol and COMT was validated with independent assays including targeted mass spectrometry and immunostaining. Celastrol bound to both soluble isoform S-COMT and membrane-bound form MB-COMT and inhibited the enzymatic activities of both isoforms. Cysteine 157 of S-COMT was found to be the primary binding site of celastrol. The conversion of dopamine (DA) to its downstream metabolite 3-methoxytyramine (3-MT), a process catalyzed by COMT, was inhibited by celastrol in neuroendocrine chromaffin cells. Our study not only revealed a novel binding target of celastrol, but also provided a new scaffold and cysteine hot spot for developing new generation COMT inhibitors in combating neurological disorders.

Reference:

1. Newman, D. J.; Cragg, G. M. J Nat Prod. 2020, 83, 770-803.
2. Corson, T. W.; Crews, C. M. Cell. 2007, 130, 769-774. 
3. Guo, H.; Yang, Y.; Zhang, Q.; Deng, J. R.; Yang, Y.; Li, S.; So, P. K.; Lam, T. C.; Wong, M. K.; Zhao, Q. ACS Chem Biol. 2022, 17, 2003-2009.