Good news! This could become a powerful new treatment option! This seems to be very promising.
"Now, a new study ... 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. ...
the study shows how to reprogram a protease from botulinum toxin to target α-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,” ...
To reprogram this precision for α-Synuclein, the research team modified the enzyme using directed evolution, a laboratory process that involves introducing mutations and selecting variants with improved function over multiple cycles.
The result: Protease 5. The challenge, however, wasn’t just reprogramming the protease to target α-Synuclein—it was ensuring that it attacked only α-Synuclein and nothing else. Past attempts to evolve proteases for therapeutic use have resulted in enzymes that targeted too broad a range of proteins, cleaving multiple unintended molecules and causing toxicity in cells.
“α-Synuclein is an incredibly hard protein to target because it doesn’t have a stable structure,” ...
Although α-Synuclein plays a central role in Parkinson’s disease and related disorders, it was used in this study as a model protein representing a broader class known as intrinsically disordered proteins (IDPs)—proteins that lack a defined shape and are notoriously difficult to target with drugs. This instability makes such illnesses challenging to treat because traditional therapies typically work by attaching to stable pockets on proteins, like a key fitting inside a lock. However, α-Synuclein has no such binding site, leaving few viable treatment options. “That’s where proteases come in,” ... “Instead of needing a specific binding site, they can be engineered to recognize and cut α-Synuclein directly, preventing it from dangerously accumulating in the brain.”
Using directed evolution, the team stepwise modified the botulinum protease, selecting variants that showed increasing preference for α-Synuclein. “Directed evolution works like selective breeding—just as farmers breed plants for better crops, scientists guide proteins through many small changes, choosing the best version at each step,” ... “Each round of modifications made the enzyme more specialized,” ... “until it could selectively degrade α-Synuclein while leaving other proteins untouched.”
When tested in human cells, Protease 5 nearly eliminated all α-Synuclein proteins, suggesting it could help prevent the harmful buildup seen in Parkinson’s disease. And because the enzyme was designed to precisely target α-Synuclein, it didn’t cause toxicity or disrupt essential cellular functions. ..."
From the significance and abstract:
"Significance
The ability to evolve proteases that selectively cleave a desired protein in vivo could provide access to useful therapeutic agents.
This would be especially powerful when targeting intrinsically disordered proteins (IDPs), a hard-to-drug class of proteins involved in many human diseases including cancer and neurodegenerative diseases.
Here, we demonstrate the stepwise evolution of clinically used botulinum protease to proteolyze the IDP α-Synuclein which forms plaques in the brains of patients suffering from Parkinson’s disease.
Abstract
There is considerable interest in the targeted degradation of proteins implicated in human disease.
The use of sequence-specific proteases for this purpose is severely limited by the difficulty in engineering the numerous enzyme–substrate interactions required to yield highly selective proteases while maintaining catalytic activity.
Herein, we report a strategy to evolve a protease for the programmed degradation of α-Synuclein, a presynaptic protein closely linked to Parkinson’s disease. Our structure-guided evolution campaign uses the protease from botulinum neurotoxin and showcases the stepwise change of specificity from its native substrate SNAP25 to the selective degradation of α-Synuclein.
The protease’s selectivity is further demonstrated in human cells where near complete degradation of overexpressed human α-Synuclein is observed with no significant effects on cell proliferation. This stepwise strategy may serve as a general approach to evolve highly selective proteases targeting dysregulated proteins."
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