Targeting STING with covalent small-molecule inhibitors.

Abstract

Aberrant activation of innate immune pathways is associated with a variety of diseases. Progress in understanding the molecular mechanisms of innate immune pathways has led to the promise of targeted therapeutic approaches, but the development of drugs that act specifically on molecules of interest remains challenging. Here we report the discovery and characterization of highly potent and selective small-molecule antagonists of the stimulator of interferon genes (STING) protein, which is a central signalling component of the intracellular DNA sensing pathway1,2. Mechanistically, the identified compounds covalently target the predicted transmembrane cysteine residue 91 and thereby block the activation-induced palmitoylation of STING. Using these inhibitors, we show that the palmitoylation of STING is essential for its assembly into multimeric complexes at the Golgi apparatus and, in turn, for the recruitment of downstream signalling factors. The identified compounds and their derivatives reduce STING-mediated inflammatory cytokine production in both human and mouse cells. Furthermore, we show that these small-molecule antagonists attenuate pathological features of autoinflammatory disease in mice. In summary, our work uncovers a mechanism by which STING can be inhibited pharmacologically and demonstrates the potential of therapies that target STING for the treatment of autoinflammatory disease.

• Authors: Simone M Haag, Muhammet F Gulen, Luc Reymond, Antoine Gibelin, Laurence Abrami, Alexiane Decout, Michael Heymann, F Gisou van der Goot, Gerardo Turcatti, Rayk Behrendt, Andrea Ablasser
• Journal: Nature (Nature) Vol. 559 Issue 7713 Pg. 269-273 (07 2018) ISSN: 1476-4687 [Electronic] England
• PMID: 29973723 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Membrane Proteins
• STING1 protein, human
• Small Molecule Libraries
• Sting1 protein, mouse
• Cysteine

Topics

• Animals
• Binding Sites
• Cell Line
• Cysteine (metabolism)
• Golgi Apparatus (drug effects, metabolism)
• Hereditary Autoinflammatory Diseases (drug therapy, metabolism)
• Humans
• Lipoylation (drug effects)
• Membrane Proteins (antagonists & inhibitors)
• Mice
• Mice, Inbred C57BL
• Protein Binding (drug effects)
• Signal Transduction (drug effects)
• Small Molecule Libraries (analysis, chemistry, metabolism, pharmacology)