A team of researchers is trying to develop a treatment for chronic inflammatory disorders by inhibiting a complex called the NLRP3 inflammasome, which is an important player in inflammation. An inhibitory molecule has already been created - MCC950; now researchers have demonstrated how it works, moving the drug one step closer to the clinic. The findings have been reported in Nature Chemical Biology and are outlined in the following video.
Inflammation is an important part of the body’s natural response to injury and microbial infection. But it has to be controlled carefully; too much inflammation can cause health problems and disease.
"Inflammation helps our bodies heal following infection, but when the inflammasome is not switched off, inflammation becomes damaging," said one of the study leaders, Dr. Rebecca Coll of the Institute for Molecular Bioscience at the University of Queensland (UQ). "Uncontrolled inflammation results in chronic diseases, such as Parkinson's disease, Alzheimer's disease, and respiratory diseases such as asthma."
"We previously identified a small molecule, MCC950, that inhibits the inflammasome to block inflammation in disease but, until now, we did not understand how it worked," explained another study leader, Associate Professor Kate Schroder of UQ's Institute for Molecular Bioscience. "We discovered that MCC950 binds directly to the inflammasome and inactivates it, turning off inflammation. Now that we understand how a small molecule can inhibit the inflammasome, we are very excited about the potential of inflammasome inhibitors as anti-inflammatory drugs."
In this work, the researchers found that MCC950 interacts with a very specific part of one domain of NLRP3, the Walker B motif. In doing so, it halts the formation of the inflammasome by preventing the hydrolysis of ATP.
"UQ start-up Inflazome Ltd, which is developing targeted therapies for inflammatory diseases, had announced its plans to commence clinical trials of their inflammasome inhibitors in 2019, and other companies are competing in this space," added study co-leader Professor Avril Robertson of UQ's School of Chemistry and Molecular Biosciences. "We are keen to see results of these trials and hope that our discovery can lead to the efficient design of new molecules as anti-inflammatory drugs of the future."