Researchers at the University of Washington's Institute for Protein Design have used computational design methods to create synthetic proteases—enzymes that cut proteins at selected sites. Two studies published in Nature on October 14 report different enzyme designs and show them working in controlled laboratory experiments. 1 3
Two designs, different catalytic strategies
One study focused on cysteine proteases, which use an activated cysteine molecule as the catalytic “blade.” Of 69 designs tested, 13 showed the intended activity. The most active design accelerated its target reaction by as much as 30 million times compared with the uncatalyzed reaction. The team also reported that the designed enzymes could cleave their targets in cultured mammalian cells. 2
A second study designed metalloproteases that use a bound metal ion in the catalytic site. Thirty-six percent of 135 designs cut their intended peptide target. The researchers also designed proteases to target TDP-43, amyloid-beta, and serum amyloid A—proteins associated with diseases including ALS, Alzheimer’s, and inflammatory conditions. The paper reports rate enhancements of up to a billion-fold for these disease-associated targets. 3
Unlike a conventional binding drug, an enzyme can act on multiple target molecules before it is spent. That makes programmable protein-cutting an interesting research direction, but the experiments do not establish that a treatment can be safely delivered or controlled in a patient. 1
A research milestone, not a therapy
The results address a longstanding design challenge: arranging an enzyme’s active site and target so that it cuts the intended protein bond with precision. The UW team says the work used deep-learning-based methods to generate candidate structures, followed by screening and experimental validation. 1
The evidence is still preclinical. The studies report purified-protein experiments and cell-culture results, not tests in people or approved therapies. GeekWire notes that researchers still need to address issues such as immune reactions and how to control a therapeutic protease’s activity. Any medical application would require further testing for selectivity, delivery, safety, and efficacy. 4
For now, the significance is a new protein-design capability: researchers can begin building enzymes to act on chosen protein sequences, including targets that are difficult to address with drugs that only bind to them.
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