EPFL scientists have discovered two small-molecule compound series that can effectively block a central pathway of the innate immune system. The innate immune system is the first line of defense, with cells that identify “foreign” motifs from viruses and bacteria and mount up a counterattack to kill them.

The cells of the innate immune system use receptors to detect pathogens, identify microbial DNA and activate a protein- 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. The lab of Andrea Ablasser at EPFL has discovered first-in-class compounds that specifically bind STING and effectively block its activity.

The team used a screening assay to find molecules that can suppress STING-mediated cellular activation. From these they extracted two separate compound series that can block STING, both in human and in mouse cells.
Researchers mutated several of the amino acids that make up STING in order to find out which ones are targeted by the compounds.

They identified a conserved transmembrane cysteine, which binds to the compounds irreversibly. As a consequence of this interaction, this particular cysteine residue can no longer undergo palmitoylation-a post-translational modification that attaches a fatty acid (palmitic acid) to STING. When STING was activated during the experiments, it assembled into multimeric clusters – a well-known effect of palmitoylation.

Scientists used the compounds to treat mice with mutations that constitutively activate STING, thereby producing autoinflammatory disease similar human’s. Treatment with either compound class significantly reduced key pathogenic features in mice. An in vitro test on cultured human cells with these small-molecules also showed efficacy to block the human version of STING further supporting therapeutical potential of these compounds in humans.
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