Enzyme engineering: New method selectively destroys disease-causing proteins

Scientists have long struggled to target proteins that lack defined structure and are involved in cancer, neurodegenerative disorders like Parkinson's disease, and other serious illnesses.

Now, a new study from Scripps Research demonstrates a proof of concept for a new strategy: engineering proteases – enzymes that cut proteins at specific sites – to selectively degrade these elusive targets with high precision in the proteome of human cells.

Published on March 24, 2025, in the Proceedings of the National Academy of Sciences, the study shows how to reprogram a protease from botulinum toxin to target ?-Synuclein – a protein with unstructured regions used here as a model. The study marks one proof point in a broader approach that could be applied to a wide range of targets across the proteome.

"This work highlights how we can use the power of laboratory evolution to engineer proteases that offer a new way to treat diseases caused by hard-to-target proteins," says senior author Pete Schultz, the President and CEO of Scripps Research, where he also holds the L.S. "Sam" Skaggs Presidential Chair. "It's an exciting step toward developing new therapeutic strategies for diseases that lack effective treatments."

The research builds on botulinum toxin, a bacterial protein best known for its use in Botox, a medication utilized for cosmetic purposes and certain medical conditions. This toxin naturally contains a protease. In its original form, the protease only targets SNAP-25 – a protein essential for transmitting signals between nerve cells. By degrading SNAP-25, botulinum toxin disrupts nerve signaling, leading to the temporary paralysis effect seen after Botox treatments.

Image source: Scripps Research.