Small-molecule–mediated precision protein editing in living cells

 While genome editing technologies have revolutionized biology, a key gap remains: the lack of methods for direct, site-specific single amino acid editing in endogenous proteins. The ability to directly and precisely manipulate native proteins without altering their underlying genetic code represents a longstanding unmet challenge in chemical biology. Here, we present LIDAPE, a modular technology designed to tackle this issue.

Inspired by natural enzymes, this LIDAPE platform integrates a target-specific binding module with a photocatalytic warhead. Upon visual light activation, the warhead catalyzes the hydrodecarboxylation of the proximal aspartate side chain, converting aspartate to alanine. Applying this technology to the kinase CDK2, we integrated a CDK2-specific binding moiety with the warhead. The resulting small molecule successfully achieved site-specific conversion of the critical aspartic acid (D145) to alanine (A145) with up to 86.7% efficiency, while leaving the other 15 apartate and glutamate residues largely unchanged. Structural and computational analyses revealed that this precision is driven by a photo-induced radical hydrodecarboxylation reaction, facilitated by water molecule network rearrangement within the ATP-binding pocket. Remarkably, the editors act catalytically and function even in complex living cell environments.

  This breakthrough may elevate small-molecule drugs from traditional "physical occupation" to precise "chemical transformation", paving the way for next-generation protein-editing therapeutics. The work titled “Small-Molecule–Mediated Precision Protein Editing in Living Cells” was published in Vita.