Novel molecules developed by researchers at the Rockefeller University (NY, USA) have the potential to provide treatments for the millions of people who suffer from an autoimmune disorder.

Reported recently in Nature Communications, Thomas Tuschl (Professor at Rockefeller University; NY, USA) and his fellow researchers from have developed small molecules that can bind to and inhibit one of the main enzymes implicated in autoimmune diseases.

Autoimmune disorders consist of a vast range of conditions, including Type I diabetes, lupus and multiple sclerosis, which are often very difficult to treat. They arise when the immune system mistakes normal cells for the typically malicious invaders the immune system targets (i.e. viruses or dangerous bacteria) and causes the body to behave in a self-destructive manner – attacking its own cells.

In 2013, researchers discovered an enzyme, cyclic GMP-AMP synthase (cGAS) that detects and binds cytosolic DNA. This initiates a cascade of cellular signaling events that results in immune activation and ends with the destruction of the DNA-shedding pathogen.

Despite the fact that the detection of DNA in the cytosol triggers the immune system – as it assumes the genetic material must have been leaked by an invading bacterium or virus – cytosolic DNA isn’t always a sign of infection. It can be produced by the body’s own cells and since cGAS cannot differentiate between infectious and innocuous DNA, the enzyme binds to cytosolic DNA, even in the absence of an intruder.

“There is no specificity. So in addition to sensing foreign microbial DNA, cGAS will also sense aberrant cytosolic DNA made by the host,” commented postdoctoral associate, Lodoe Lama. “And this lack of self versus non-self specificity could be driving autoimmune reactions.”

Following on from this discovery, researchers at the Tuschl laboratory hypothesized if autoimmune disorders are the result of an erroneously activated immune system, then a cGAS inhibitor could potentially be used to treat these conditions.

From their work, they have identified potential inhibitors. In a collaborative effort with Rockefeller’s High-Throughput and Spectroscopy Resource Center (NY, USA), they scanned a library of almost 300,000 small molecules and found two that have shown some activity against human cGAS.

Prior to this, no potent and specific small molecule compound had been found against cGAS in humans, only in mouse cells.

“The hits from library compounds were a great starting point, but they were not potent enough,” explained Lama. “So we used them as molecular scaffolds on which to make improvements, altering their structures in ways that would increase potency and also reduce toxicity.”

Working with the Tri-Institutional Therapeutics Discovery Institute (NY, USA) the researchers modified on of their original scaffolds to create three compounds that blocked cGAS activity in human cells – the first molecule with this capability. Upon further analysis by researchers at Memorial Sloan Kettering Cancer Center (NY, USA) revealed the compounds to inhibit cGAS by wedging into a pocket of the enzyme that is key to its activation.

Now, these compounds are being further optimized for potential use in patients, with an initial focus on treatment of the rare, genetic disease, Aicardi-Goutières syndrome. This condition leads to severe neurological problems, due to the accumulation of abnormal cytosolic DNA and aberrant activation of cGAS.

“This class of drug could potentially also be used to treat more common diseases, such as systemic lupus erythematosus, and possibly neurodegenerative diseases that include inflammatory contributions such as Parkinson’s disease,” added Tuschl.

Additionally, the researcher believe that these compounds have the potential to serve as practical laboratory tools. “Scientists will now have simple means by which to inhibit cGAS in human cells,” concluded Lama. “And that could be immensely useful for studying and understanding the mechanisms that lead to autoimmune responses.”