New small molecules pave the way for treating autoinflammatory disease

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.

Now, 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.

To find out the compounds' mechanism of action, the researchers painstakingly mutated several of the amino acids that make up STING in order to find out which ones are targeted by the compounds. Doing so, the scientists 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.

Although we don't know exactly how this chemical process connects to the activity of STING, the scientists observed that when STING was activated in the course of their experiments, it assembled into multimeric clusters - a well-known effect of palmitoylation. This observation adds evidence that palmitoylation is required for STING to perform its role during innate immune responses, presenting another potential target for blocking STING in the context of autoinflammatory disease.

Finally, the team carried out proof-of-concept pre-clinical studies to test the effect of the compounds on actual autoinflammatory diseases. For this, the scientists used the compounds to treat mice with mutations that constitutively activate STING, thereby producing a type of autoinflammatory disease similar to some seen in humans.

In an exciting finding, treatment with either compound class significantly reduced key pathogenic features in mice. Of importance, 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. However, confirmation of this effect would require formal clinical trials.

The discovered compounds are described as "small molecules", which is a term used for molecules with low molecular weight and up to a nanometer in size. In fact, most drugs are small molecules, meaning that the discovered compounds show promise for drug development.

"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."

With EPFL, the authors have filed provisional patent applications related to STING inhibitors.

Simone M Haag, Muhammet F Gulen, Luc Reymond, Antoine Gibelin, Laurence Abrami, Alexiane Decout, Michael Heymann, Gisou F van der Goot, Gerardo Turcatti, Rayk Behrendt, Andrea Ablasser.
Targeting STING with covalent small-molecule inhibitors.
Nature 04 July 2018. DOI: 10.1038/s41586-018-0287-8.

Most Popular Now

Walnuts may help lower blood pressure for those at…

When combined with a diet low in saturated fats, eating walnuts may help lower blood pressure in people at risk for cardiovascular disease, according to a new Penn State ...

Bristol-Myers Squibb reports first quarter financi…

Bristol-Myers Squibb Company (NYSE:BMY) today reported results for the first quarter of 2019 which were highlighted by strong demand for Opdivo (nivolumab) and Eliquis (a...

Amgen ignites a social fitness movement to support…

Amgen (NASDAQ:AMGN) launched the Breakaway Challenge initiative, a national social fitness program to motivate individuals to take action in their health and to support t...

Possible link between autism and antidepressants u…

An international team led by Duke-NUS Medical School has found a potential link between autistic-like behaviour in adult mice and exposure to a common antidepressant in t...

AstraZeneca starts artificial intelligence collabo…

AstraZeneca and BenevolentAI today began a long-term collaboration to use artificial intelligence (AI) and machine learning for the discovery and development of new treat...

Researchers define Alzheimer's-like brain disorder

A brain disorder that mimics symptoms of Alzheimer's disease has been defined with recommended diagnostic criteria and guidelines for advancing future research on the con...

Comprehensive tumor profiling promises new therape…

The WINTHER trial, NCT01856296, led by investigators from Vall d'Hebron Institute of Oncology - VHIO (Spain), Chaim Sheba Medical Center (Israel) (Raanan Berger), Gustave...

Amgen and Syapse enter precision medicine collabor…

Amgen (NASDAQ:AMGN), a world leader in biotechnology, and Syapse, a company powering precision medicine insights through its global provider network, announced a precisio...

Drugs to prevent stroke and dementia show promise …

Treatments that prevent recurrence of types of stroke and dementia caused by damage to small blood vessels in the brain have moved a step closer, following a small study...

Novartis presents first-of-its-kind algorithm-base…

Novartis today announced results from a validation study of the innovative, algorithm-based digital solution MS Progression Discussion Tool, or MSProDiscussTM. The tool a...

Trastuzumab deruxtecan demonstrated clinically-mea…

AstraZeneca and Daiichi Sankyo Company, Limited (Daiichi Sankyo) today announced positive top-line results for the pivotal Phase II DESTINY-Breast01 trial of trastuzumab ...

Genetic therapy heals damage caused by heart attac…

Researchers from King's College London have found that therapy that can induce heart cells to regenerate after a heart attack. Myocardial infarction, more commonly known ...