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Targeting STING with covalent small-molecule inhibitors.
Simone M Haag1, Muhammet F Gulen1, Luc Reymond2
1Global Health Institute, Swiss Federal Institute of Technology Lausanne (EPFL), Lausanne, Switzerland.
Nature
|July 6, 2018
Summary
Researchers discovered small molecules that block the stimulator of interferon genes (STING) protein, a key player in innate immunity. These STING inhibitors reduce inflammation and show potential for treating autoinflammatory diseases.
Area of Science:
- Immunology
- Molecular Biology
- Drug Discovery
Background:
- Aberrant innate immune pathway activation is linked to various diseases.
- Targeted therapies for innate immunity are promising but challenging to develop.
- The stimulator of interferon genes (STING) protein is a critical mediator of intracellular DNA sensing.
Purpose of the Study:
- To discover and characterize novel small-molecule antagonists of the STING protein.
- To elucidate the mechanism by which STING antagonists inhibit its function.
- To evaluate the therapeutic potential of STING inhibition in autoinflammatory disease models.
Main Methods:
- Discovery and characterization of small-molecule STING antagonists.
- Investigation of STING inhibition mechanism, including targeting cysteine 91 and blocking palmitoylation.
- Assessment of STING inhibitor efficacy in reducing cytokine production in human and mouse cells.
- Evaluation of STING antagonists in mouse models of autoinflammatory disease.
Main Results:
- Identification of potent and selective small-molecule STING antagonists.
- Demonstration that these compounds covalently target cysteine 91, inhibiting STING palmitoylation.
- Evidence that STING palmitoylation is crucial for multimeric complex assembly and downstream signaling.
- Reduction of STING-mediated inflammatory cytokine production in vitro.
- Attenuation of pathological features in a mouse model of autoinflammatory disease.
Conclusions:
- STING palmitoylation is essential for its function and can be pharmacologically inhibited.
- Small-molecule STING antagonists represent a promising therapeutic strategy for autoinflammatory diseases.
- This work provides a novel mechanism for STING inhibition and its therapeutic application.
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