A recent research study examined a library of almost 300,000 small molecules to search for a molecule that may be a potential target for the human GMP-AMP synthase (cGAS)—an enzyme that can detect and bind to cytosolic DNA and initiating a chain reaction leading to immune activation with the result of the destruction of the DNA-shedding pathogen.
Through their initial screening, researchers were able to identify two molecules that showed some activity against cGAS.
“The hits from library compounds were a great starting point, but they were not potent enough,” said postdoctoral associate Lodoe 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.”
In collaboration with Tri-Institutional Therapeutics Discovery Institute, scientists created three compounds that inhibited cGAS activity in human cells. Further analytical studies by researchers at Memorial Sloan Kettering Cancer Centre showed that compounds block cGAS activation by wedging into a critical pocket.
The significance of inhibiting cGAS would be of critical therapeutic relevance to those with autoimmune diseases who have few treatment options. Currently, compounds are being optimized for prospective use in patients particularly those diagnosed with a rare genetic disease called Aicardi-Goutières syndrome. Individuals with Aicardi-Goutières syndrome have an abnormal accumulation of cytosolic DNA that activates cGAS and can lead to serious neurological problems.
“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,” adds Thomas Tuschl, Ph.D.
Findings of the study, as reported in Nature Communications, sheds light on the causes of autoimmunity.
“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.”
Source: Drug Target Review