Cell death drug discovery: come at the king, you best not miss

It may seem like a stretch to compare an enzyme to a notorious criminal, especially one as distinctive as Omar Little, a character from the HBO drama The Wire played by Michael Kenneth Williams.

But stick with me, I’ll explain.

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Omar is a stick-up man who robs street-level drug dealers. When drug dealer henchmen Stinkum and Weebay ambush him, they are unsuccessful and Stinkum is killed. Omar tells Weebay, who is hiding behind a car: “Come at the king, you best not miss.”

At Emory, Ed Mocarski, Bill Kaiser and colleagues at GlaxoSmithKline have been studying an enzyme called RIP3. RIP3 is the king of a form of programmed cell death called necroptosis. RIP3 is involved in killing cells as a result of several inflammation-, infection- or injury-related triggers, so inhibitors of RIP3 could be useful in modulating inflammation in many diseases.

In a new Molecular Cell paper, Mocarski, Kaiser and their co-authors lay out what happened when they examined the effects of several compounds that inhibit RIP3 in cell culture. These compounds stopped necroptosis, but unexpectedly, they unleashed apoptosis, another form of programmed cell death. 

The chemical inhibitors apparently lead RIP3 to aggregate and cause the assembly of a separate “death machine.” Necroptosis and apoptosis are both forms of programmed cell death, but they appear different microscopically and are dependent on different sets of cellular components.

Omar does eventually meet his end. Similarly, the researchers show that it is possible to kill RIP3’s enzymatic activity in genetically engineered mice without disturbing their development. The protein is left in place, but the kinase enzyme activity is dead. Drug discovery efforts need to take RIP3’s dual nature into account, the authors write:

“Going forward, therapeutic strategies that directly target RIP3 kinase activity certainly must avoid the conformational changes that unleash RHIM signaling and nucleate Casp8-mediated apoptosis.”

For a taste of the broad potential applications of this research, the authors write that “RIP3-dependent necrotic death is crucial for inflammation, an association that has been extended to infection, ischemia reperfusion, sepsis, macular degeneration, neurodegenerative disorders, pancreatitis, gastroenteritis, and dermatitis.”

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Posted on by Quinn Eastman in Immunology Leave a comment

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Quinn Eastman

Science Writer, Research Communications qeastma@emory.edu 404-727-7829 Office

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