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- Title
Marine diterpenoid targets STING palmitoylation in mammalian cells.
- Authors
Hsiao, Wan-Chi; Niu, Guang-Hao; Lo, Chen-Fu; Wang, Jing-Ya; Chi, Ya-Hui; Huang, Wei-Cheng; Tung, Chun-Wei; Sung, Ping-Jyun; Tsou, Lun Kelvin; Zhang, Mingzi M.
- Abstract
Natural products are important sources of therapeutic agents and useful drug discovery tools. The fused macrocycles and multiple stereocenters of briarane-type diterpenoids pose a major challenge to total synthesis and efforts to characterize their biological activities. Harnessing a scalable source of excavatolide B (excB) from cultured soft coral Briareum stechei, we generated analogs by late-stage diversification and performed structure-activity analysis, which was critical for the development of functional excB probes. We further used these probes in a chemoproteomic strategy to identify Stimulator of Interferon Genes (STING) as a direct target of excB in mammalian cells. We showed that the epoxylactone warhead of excB is required to covalently engage STING at its membrane-proximal Cys91, inhibiting STING palmitoylation and signaling. This study reveals a possible mechanism-of-action of excB, and expands the repertoire of covalent STING inhibitors. Excavatolide B (excB) is a marine briarane type diterpenoid with anti-inflammatory properties, however, its cellular targets and mode-of-action remain unknown. Here, the authors develop two covalent probes of excB and apply them through a chemoproteomics approach to identify STING as a direct target of excB in living mammalian cells.
- Subjects
PALMITOYLATION; DRUG discovery; ALCYONACEA; NATURAL products; PROTEOMICS; INTERFERONS; DITERPENES; MOLECULAR probes
- Publication
Communications Chemistry, 2023, Vol 6, Issue 1, p1
- ISSN
2399-3669
- Publication type
Article
- DOI
10.1038/s42004-023-00956-9