Marine diterpenoid targets STING palmitoylation in mammalian cells

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. 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.

Automated summary

In this study, two covalent probes were developed to identify STING as a direct target of excB in living mammalian cells. The study reveals a possible mechanism-of-action of excB and expands the repertoire of covalent STING inhibitors.