Research could lead to new treatments for people with autoimmune disorders

The immune system is programmed to rid the body of biological criminals – such as viruses and dangerous bacteria – but its accuracy is not guaranteed. On tens of millions of Americans suffering from autoimmune diseases, the system confuses normal cells with malicious invaders, prompting the body to adopt self-destructive behavior. It is very difficult to treat this diverse clbad of diseases, including type I diabetes, lupus and multiple sclerosis.

In a new report in Nature Communications, Researchers at Thomas Tuschl's lab describe the development of small molecules that inhibit one of the major enzymes involved in unhealthy immune responses. This research could lead to new treatments for people with certain autoimmune diseases and, more broadly, shed light on the causes of autoimmunity.

Cellular security

In eukaryotes, including humans, the DNA usually resides in the nucleus of a cell or in other sequestered organelles such as mitochondria. So, if the DNA is outside these compartments – in the cytosol of the cell – the immune system goes into maximum alert, baduming that the genetic material has been filtered by an invading bacterium or virus.

In 2013, researchers discovered an enzyme called cyclic GMP-AMP synthase, or cGAS, that detects cytosolic DNA and binds to it to trigger a chain reaction, a cascade of cellular signaling events. leading to an immune activation that usually end in the destruction of the virus. Pathogen that destroys DNA.

However, cytosolic DNA is not always a sign of infection. Sometimes it is produced by the body's own cells – and cGAS does not distinguish between infectious DNA and harmless DNA. The enzyme will bind to a perfectly harmless genetic material, causing an immune response even in the absence of intruders.

There is no specificity. Thus, in addition to detecting foreign microbial DNA, cGAS will also detect aberrant cytosolic DNA made by the host. And this lack of self-specificity in relation to a non-specificity of oneself could be at the origin of autoimmune reactions. "

Postdoctoral Associate Lodoe Lama

Since the discovery of cGAS, researchers at Tuschl have sought to understand its potential clinical relevance. If autoimmune disorders result from an immune system activated by mistake, then, they may believe that a cGAS inhibitor could be used to treat these conditions.

Until now, there was no potent, small molecule specific compound to block cGAS in human cells, although researchers have previously identified one that can do the work in mouse cells. In the hope of filling this gap, the Tuschl team collaborated with Rockefeller's Broadband and Spectroscopy Resource Center to browse a library of nearly 300,000 small molecules, searching of the one that could target the human cGAS.

Build a blocker

Through their screening, the researchers identified two molecules that exhibited some activity against cGAS – but this result was only the beginning of a long process to develop an inhibitor that could be used clinically.

"The library hits were a good starting point, but they were not powerful enough," says Lama. "So we used them as molecular scaffolds to make improvements, modifying their structures to increase potency and reduce toxicity."

In collaboration with the Tri-Institutional Therapeutics Discovery Institute, researchers have modified one of their original scaffolds to create three compounds blocking the activity of cGAS in human cells – thus making the first molecules with this ability. Additional badyzes by researchers at the Memorial Sloan Kettering Cancer Center revealed that the compounds inhibit cGAS by inserting into a pocket of the enzyme that is key to its activation.

The compounds are being optimized for potential use in patients, initially focusing on the treatment of the rare genetic disease of Aicardi-Goutières syndrome. People with this disease accumulate abnormal cytosolic DNA that activates cGAS, leading to serious neurological problems. A drug that blocks the enzyme would therefore have a huge therapeutic value for people with the disease, who currently have few treatment options.

"This clbad of drugs could potentially also be used to treat more common diseases, such as systemic lupus erythematosus, and possibly neurodegenerative diseases with inflammatory reactions, such as Parkinson's disease," Tuschl says.

In addition, researchers believe that these compounds could be useful laboratory tools.

"Scientists will now have simple ways to inhibit cGAS in human cells," said Lama. "And this could be extremely useful for studying and understanding the mechanisms that lead to autoimmune responses."

Source:

Rockefeller University

Journal reference:

Tuschl, T. et al. (2019) Development of cGAS-specific human small molecule inhibitors for the suppression of dsDNA-mediated expression of interferon. Nature Communications. doi.org/10.1038/s41467-019-08620-4