Small molecule 'jams the switch' to prevent inflammatory cell death

Walter and Eliza Hall Institute scientists have discovered a small molecule that blocks a form of cell death that triggers inflammation, opening the door for potential new treatments for inflammatory disease such as rheumatoid arthritis, Crohn's disease and psoriasis.

The researchers made the discovery while investigating how a protein called MLKL kills cells in a process known as necroptosis. Their findings were published today in the journal Proceedings of the National Academy of Sciences.

Necroptosis is a recently discovered cell death pathway linked to immune disorders. It is a vital process in which cells undergo programmed death while warning the immune system that something has gone wrong, such as during viral infection. However when necroptosis is inappropriately activated, it can promote inflammation and the development of inflammatory disease.

Dr Joanne Hildebrand, Ms Maria Tanzer, Dr James Murphy, Associate Professor John Silke from the Cell Signalling and Cell Death division and institute colleagues studied how MLKL changes shape to trigger cell death. "MLKL is the final protein in the cell death pathway but it needs to be activated before it can kill the cell," Dr Hildebrand said. "Understanding how it becomes active can help uncover new ways to treat disease."

Dr Hildebrand said the research team found that a particular part of the protein became 'unlatched' when activated, allowing it to attach to the cell membrane and trigger cell death. "It's like flicking a molecular switch," she said. "We showed that when the switch can't be 'turned on', MLKL doesn't become active and necroptosis is prevented."

The researchers worked with Dr Isabelle Lucet, Associate Professor Guillaume Lessene and colleagues from the ACRF Chemical Biology division to discover a small molecule that could block the action of MLKL.

Ms Tanzer said the team tested a range of small molecules to see if any could stop the switching on of MLKL and had identified one that prevented MLKL from becoming active. "This small molecule binds to MLKL in such a way that it 'jams the switch' that makes it active," she said. "We are really excited by this discovery because not only have we shown this particular part of the protein is essential for necroptosis, we also have a starting point in a drug discovery program."

Institute scientists would now embark on a collaborative project with Catalyst Therapeutics to develop a potent new drug based on the small molecule identified in the study, Dr Murphy said. "MLKL is an appealing target because research suggests it does only one thing, which is kill the cell," he said. "Blocking this protein doesn't impact other functions of the cell, reducing the chance of unwanted side-effects."

"If we can create a compound that better targets this particular part of MLKL, we can prevent necroptosis and improve treatments for inflammatory disease."