The lysosomal degradation pathway has a wide range of applicability, including but not limited to proteins, protein multimers, organelles, etc. Lysosome-targeting chimera (LYTAC) is a protein degradation technology using the endosomal-lysosomal system. Similar to the structure of PROTAC, LYTAC is a bifunctional molecule consisting of two binding ligands, one of which is an oligosaccharide structure targeting the lysosome-targeting receptors (LTRs) on the cell surface, and the other could be an antibody, peptide or small molecule targeting the protein of interest (POI), which are chemically conjugated by a linker.
First, the POI ligand of LYTAC binds to the extracellular domain of the POI, while the oligosaccharide structure binds to the LTRs on the cell surface, forming the LTRs-LYTAC-POI ternary complex; Sequentially, the complex enters the cell via clathrin-mediated endocytosis (CME), and passes sequentially through the vesicles to the early endosome (EE) and late endosome (LE); With endosome acidification, the LTRs in the ternary complex dissociates and returns to the cell membrane or Golgi apparatus, and the binding of LYTAC and the target protein is continued to be transported to the lysosome for degradation.
LYTAC is designed to be bound to POI at one end and recognized by LTR at the other end. Three choices of POI-binding ligands are available, including antibodies, peptides, and small molecules. LTR-binding ligands include PolyM6Pn and Tri-GalNAc, which target the mannose-6-phosphate receptor (CI-M6PR) and the asialoglycoprotein receptor (ASGPR), members of the LTR family, respectively.
