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Researchers design protein scissors that cut specific targets

Researchers design protein scissors that cut specific targets

New Capabilities

Computationally designed proteases cut chosen sites in disease-linked proteins in lab tests, but none has reached animals or patients

October 14th, 2026: Nature publishes cysteine protease design paper

Overview

Updated Oct 27

University of Washington researchers designed protein-cutting enzymes from scratch. Each one snips a chosen protein at a chosen point. In one study, the enzymes cut a reporter protein inside cultured human cells, and one design cut full-length TDP-43, a protein tied to ALS.

A cysteine-based design sped up cutting by as much as 30 million times over the uncatalyzed reaction. A zinc-based design reached 100 million times for amyloid-beta, the Alzheimer's-linked protein. No animal or human tests have been reported. An independent preprint from Westlake University also reports designed zinc enzymes for amyloid-beta.

Why it matters

These programmable protein scissors could destroy disease proteins — Alzheimer's plaques, ALS aggregates, bacterial toxins — that no existing drug can target.

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Key Indicators

19%
Cysteine protease design success rate
13 of 69 designed enzymes cut their target sequence.
36%
Zinc protease design success rate
More than one-third of designed metalloproteases showed activity.
100 million×
Fastest bond-cleavage acceleration
Zinc protease sped peptide bond hydrolysis more than 100 million times over the uncatalyzed reaction.
0
Animal or human studies reported
Tests so far used purified proteins and cultured cells.

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People Involved

David Baker
David Baker
Director, UW Medicine Institute for Protein Design; Professor of Biochemistry, University of Washington School of Medicine
Led the protease design effort; shared the 2024 Nobel Prize in Chemistry
 Hojae Choi
Hojae Choi
Lead author of the cysteine protease study
Lead author of the cysteine protease study
AC
Anqi Chen
Lead author of the metalloprotease study
Designed zinc proteases that cut amyloid-beta
 Kejia Wu
Kejia Wu
Co-lead author of the metalloprotease study
Co-designed zinc proteases using the RoseTTAFold Diffusion model

Organizations Involved

MI
UW Medicine Institute for Protein Design
Research institute
Conducted the protease design research

University of Washington institute that computationally designs proteins, including the new synthetic proteases.
University of Washington School of Medicine
University of Washington School of Medicine
Academic medical school
Home of the researchers and the Institute for Protein Design

Academic medical school whose department of biochemistry houses the protein design work.

Timeline

3 events Latest: October 14th, 2026 · 4 weeks ago

  1. Nature publishes cysteine protease design paper

    Latest Publication

    Researchers report de novo designed enzymes using an activated cysteine to cut peptide bonds. 13 of 69 designs worked, up to 30 million times faster than the background reaction.

  2. Nature publishes zinc metalloprotease design paper

    Publication

    Designs using a bound zinc ion as the cutting blade showed activity in 36% of cases. The most active cleaved amyloid-beta 100 million times faster than the uncatalyzed reaction.

  3. UW Medicine announces designed molecular scissors

    Announcement

    The institute publicly reported the proteases with the Nature papers. It says they cut targeted proteins precisely and worked in cultured human cells, including against proteins tied to Alzheimer's and ALS.

Scenarios

1

Designed proteases reach human trials

Possible Resolves by End of 2029

Discussed by: UW Medicine researchers; the Nature papers note therapeutic promise

Researchers continue testing the proteases on disease targets, first in animal models. If safety and efficacy hold, a designed protease aimed at a neurodegenerative disease protein — amyloid-beta in Alzheimer's or TDP-43 in ALS — advances to a Phase 1 clinical trial.

2

Designed proteases become a standard research tool

Likely Resolves by Q2 2028

Discussed by: The Nature papers and UW Medicine announcement describe the work as a step toward tailor-made molecular scissors

Independent labs adopt the designed proteases for controlled protein cleavage in experiments — protein purification, studying protein degradation, and building synthetic circuits. Wide use in basic research follows, much as early CRISPR tools spread through labs.

3

Clinical development stalls on delivery and immune hurdles

Possible Resolves by End of 2029

Discussed by: Ars Technica and GeekWire coverage note delivery, immunogenicity, and switchability as barriers

Proteins are hard to deliver inside cells, may trigger immune responses, and the proteases need on/off control. If these obstacles persist, the enzymes stay research reagents and no therapy advances.

Historical Context

3 moments from history that rhyme with this story — and how they unfolded.

June 2012 – 2013

CRISPR-Cas9 genome editing (2012–2013)

In 2012, researchers including Jennifer Doudna, Emmanuelle Charpentier, and later Feng Zhang showed that a bacterial immune system called CRISPR-Cas9 could be repurposed to cut specific DNA sequences at will. A guide RNA directs the Cas9 enzyme to a precise spot in the genome.

Then

Within months, laboratories worldwide adopted CRISPR for gene editing, and it became the standard method for altering DNA.

Now

CRISPR underlies a growing field of gene therapies and engineered crops, though delivery and off-target effects remain hurdles.

Why this matters now

Like designed proteases, CRISPR is a programmable molecular scissors. It shows how a lab tool that cuts biological molecules can grow into a therapy platform — and the delivery and specificity problems it had to overcome.

October 2024

2024 Nobel Prize in Chemistry for protein design

The Royal Swedish Academy awarded the 2024 Nobel Prize in Chemistry to David Baker for computational protein design, and to Demis Hassabis and John Jumper for protein structure prediction. Baker's lab had built software that designs new proteins folding into desired shapes.

Then

The prize recognized protein design as a mature field with practical uses in medicine and materials.

Now

It cemented algorithmic protein design as a foundation for creating new molecular tools, including enzymes.

Why this matters now

This protease work extends the capability that won Baker the prize — from designing static protein shapes to designing proteins that perform chemistry.

2008 – 2010s

First de novo designed enzymes (2008–2010s)

In 2008 the Baker lab reported the first de novo designed enzyme, a Kemp eliminase that accelerates a simple reaction with a low energy barrier. Later designs tackled similar model reactions.

Then

De novo enzymes were built, but they were limited to activating relatively easy chemical bonds.

Now

The new Nature papers note that de novo enzyme design had largely succeeded only on low-energy-barrier model reactions — until now.

Why this matters now

Cleaving a peptide bond, which is stable in water for years, is a far harder target than the model reactions earlier de novo designs achieved.

Sources

(10)
+4
UW Medicine Newsroom Nature Nature Human Progress Phys.org Ars Technica GeekWire NE-CAT (Cornell University) Happened in AI BioLabs Research