LYSOSOME-TARGETING CHIMERAS FOR NEXT-GENERATION DRUG DISCOVERY AND DEVELOPMENT
DOI:
https://doi.org/10.65327/bp.v12i3.2533Keywords:
Lysosome-targeting chimeras, targeted protein degradation, lysosomal trafficking, drug discovery, precision therapeuticsAbstract
Lysosome-targeting chimeras (LYTACs) are emerging as a versatile targeted protein degradation strategy for extracellular, soluble, and membrane-associated proteins that remain difficult to address with conventional inhibitors. These bifunctional constructs connect a disease-associated target to an internalizing lysosome-shuttling receptor, promoting endocytosis, endosomal sorting, and lysosomal destruction. This review examines the molecular mechanisms, architectural components, receptor systems, linker designs, and discovery strategies governing LYTAC activity. It also evaluates developing applications in cancer, immune-mediated disorders, fibrosis, metabolic disease, neurological conditions, and infectious diseases. Antibodies, peptides, aptamers, small-molecule ligands, tissue-selective receptor binders, and engineered delivery systems provide expanding opportunities to improve target recognition and cellular specificity. However, variable receptor expression, incomplete understanding of intracellular trafficking, inconsistent degradation efficiency, limited bioavailability, immunogenicity, and non-standardized assays continue to restrict translation. Future progress will depend on programmable tissue-selective platforms, robust pharmacokinetic–pharmacodynamic evaluation, validated biomarkers, scalable manufacturing, and rational combination treatments. Optimized LYTACs may ultimately convert previously inaccessible proteins into clinically actionable targets and broaden the therapeutic scope of degradation-based drug discovery.
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