A team at UW Medicine’s Institute for Protein Design has engineered proteases that act as molecular scissors to target proteins linked to Alzheimer’s disease and ALS, using AI-developed models.

Researchers are addressing immunogenicity—the risk that the immune system will attack the therapy—and are exploring ways to control protease activity, including approaches that combine catalytic elements with antibody-like components.

The technology has potential applications beyond neurodegenerative diseases, including malaria, cancer, chronic diseases, and the possibility of defanging viruses or bacterial toxins, with even broader non-medical uses like degrading pollutants and plastic waste.

Two Nature papers from David Baker and colleagues describe proteases with two different cutting mechanisms: one uses a metal ion blade that yields exceptionally rapid cuts, and the other uses activated cysteine achieving a notable target-cutting rate and extremely fast reactions.

These proteases can cut specific targets repeatedly, enabling amplified therapeutic effects at very low drug concentrations.

Choi and team are pursuing strategies to modulate protease activity and reduce immune responses, with ongoing work described as a newly launched project with no public data yet.