Democratizing LYTACs—A Modular Click Chemistry Platform for the Rapid Assembly of Lysosome-Targeting Chimeras

Lysosome-targeting chimeras (LYTACs) are emerging therapeutics that mediate extracellular targeted protein degradation. Through simultaneous engagement of a target protein of interest and a lysosomal trafficking receptor, these bifunctional molecules can facilitate the degradation of both secreted and cell-surface proteins. The original LYTACs were designed to engage the cation-independent mannose-6-phosphate receptor (CI-M6PR) via complex glycopolymer or glycopolypeptide ligands conjugated to target-specific antibodies. However, the complexity of these ligands has limited the broader adoption of LYTACs as research tools. Here we describe a simple, rapid, and modular click chemistry platform for the generation of CI-M6PR-binding LYTACs. The approach utilizes only commercially available reagents and standard laboratory equipment and allows for the conversion of virtually any antibody into a LYTAC. This method for “democratizing” LYTAC generation should facilitate the widespread adoption of these tools for biological discovery.