Baker lab designs de novo cysteine proteases that cleave peptide bonds, published in Nature

DaveJuergens · x · 2026-10-19

• The Baker lab (corresponding author David Baker) published a Nature paper on de novo design of cysteine proteases: entirely new protein folds that cleave peptide backbones, breaking past the limitation that de novo enzyme design had largely succeeded only on low-energy-barrier model reactions.
• The workflow starts from an input catalytic motif (Cys-His-Asp triad), generates backbones via RFdiffusion-style methods, and screens designs — with an observed design success rate of about 19% (13/69 characterized designs showing cleavage). Structures span parallel, anti-parallel and sandwich β-strand pair topologies.
• The resulting enzymes (e.g. Gawi, Kal, Dokki) demonstrate activity in mammalian cells, validated by cleaving a substrate protein fused to an mScarlet reporter. Paper and code are publicly available.

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