New small molecules for the treatment of autoinflammatory diseases

Indigophoton · Jul 5, 2018

EPFL scientists have discovered two small-molecule compound series that can effectively block a central pathway of the innate immune system, offering a promising new way for treating autoinflammatory diseases. The study is published in Nature.

The innate immune system is the first line of defense, with cells that quickly identify "foreign" motifs from viruses and bacteria and mount up a counterattack to eliminate them. As a key strategy to sense the presence of pathogens, the cells of the innate immune system use receptors that can identify microbial DNA and in turn activate a protein called STING (STimulator of Interferon Genes). Once activated, STING turns on genes that help cells fight off the infecting pathogen.

Nonetheless, the innate immune system can turn against the body itself, causing a number of diseases, which are referred to as autoinflammatory. But even though the molecules involved in the innate immune system are well studied, developing drugs that act on specific molecules of interest is still a big challenge.

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"Our work uncovered an unexpected mechanism to target STING and provided the first proof-of-concept that anti-STING therapies are efficacious in autoinflammatory disease," says Andrea Ablasser. "Beyond specific monogenic autoinflammatory syndromes, the innate immune system is implicated in even broader 'inflammatory' conditions, so we are excited to learn more about the role of STING in human diseases."
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https://medicalxpress.com/news/2018-07-small-molecules-treatment-autoinflammatory-diseases.amp

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.
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https://www.nature.com/articles/s41586-018-0287-8

Woolie · Jul 6, 2018

Thanks for posting @Indigophoton. I'm especially interested because I've been diagnosed with an autoinflammatory disease. But I suspect that I'm not the only one here who has one of these diseases.

Jonathan Edwards · Jul 6, 2018

This looks of considerable interest. Blocking innate activation pathways has been hard, partly because a lot of it depends on kinases (enzymes that add phosphate tags to signalling molecules to make them active). Blocking kinases has proved very hard to get 'clean' since the 1980s. A new strategy for blocking activation of a transmembrane receptor by 'covering up' an activation site sounds clever.

I would agree with Woolie that although this is specifically relevant to auto inflammatory disease it would not be at all surprising if this pathway was involved in a non-inflammatory syndrome like ME/CFS. Interferons are involved in producing symptoms without actually creating local inflammation.

Sasha · Jul 6, 2018

Jonathan Edwards said: ↑

This looks of considerable interest. Blocking innate activation pathways has been hard, partly because a lot of it depends on kinases (enzymes that add phosphate tags to signalling molecules to make them active). Blocking kinases has proved very hard to get 'clean' since the 1980s. A new strategy for blocking activation of a transmembrane receptor by 'covering up' an activation site sounds clever.

I would agree with Woolie that although this is specifically relevant to auto inflammatory disease it would not be at all surprising if this pathway was involved in a non-inflammatory syndrome like ME/CFS. Interferons are involved in producing symptoms without actually creating local inflammation.
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How can we get people to look at this in relation to ME/CFS?

NelliePledge · Jul 7, 2018

didnt Ron Davis hint last year that he thought there was a small molecule involved? (Sorry for the Noddy level of my comment)

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New small molecules for the treatment of autoinflammatory diseases

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New small molecules for the treatment of autoinflammatory diseases

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