by Alan Gill
Ms Maria Tanzer, Dr Joanne Hildebrand (L-R) and colleagues have discovered a small molecule can prevent a key protein from triggering a form of cell death than causes inflammatory disease.
(Medical Xpress)—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 and 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."
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."
Dr Murphy said 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. "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."
Explore further: Link found between cell death and inflammatory disease
More information: The complete paper is available online: http://ift.tt/1qBcD3F 987111.full.pdf+html
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© Medical Xpress 2011-2014, Science X network
by Alan Gill
Ms Maria Tanzer, Dr Joanne Hildebrand (L-R) and colleagues have discovered a small molecule can prevent a key protein from triggering a form of cell death than causes inflammatory disease.
(Medical Xpress)—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 and 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."
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."
Dr Murphy said 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. "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."
Explore further: Link found between cell death and inflammatory disease
More information: The complete paper is available online: http://ift.tt/1qBcD3F 987111.full.pdf+html
Medical Xpress on facebook
Related Stories
Cell death protein could offer new anti-inflammatory drug target
Sep 05, 2013
Scientists in Melbourne, Australia, have revealed the structure of a protein that is essential for triggering a form of programmed cell death, making possible the development of new drugs to treat chronic inflammatory diseases ...
Link found between cell death and inflammatory disease
May 12, 2014
(Medical Xpress)—A team of Melbourne researchers has shown a recently discovered type of cell death called necroptosis could be the underlying cause of inflammatory disease.
Mechanism of cell death unraveled—perspectives for treating inflammatory diseases
Jun 04, 2014
Researchers at VIB and Ghent University have unraveled the mechanism of necroptosis. This is a type of cell death that plays a crucial role in numerous diseases, from viral infections and loss of auditory nerve cells to multiple ...
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Oct 13, 2011
The outer layer of the skin, called the epidermis, forms a critical physical and immunological wall that serves as the body's first line of defense against potentially harmful microorganisms. Most of the epidermis consists ...
Scientists identify cell death pathway involved in lethal sepsis
Dec 22, 2011
Sepsis, a form of systemic inflammation, is the leading cause of death in critically ill patients. Sepsis is linked with massive cell death; however, the specific mechanisms involved in the lethality of sepsis are unclear. ...
Recommended for you
'Virological penicillin': Plant MIR2911 directly targets influenza A viruses
3 hours ago
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Babies' gut bacteria are mostly fixed by time spent in the womb
20 hours ago
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21 hours ago
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21 hours ago
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User comments
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