"Democratizing LYTACs: enabling facile access to targeted protein degradation via mannose-6- phosphate receptor"
Extracellular and membrane proteins comprise of around 40% of disease-related protein targets, including misfolded protein aggregates, signaling factors, surface receptors, ion channels and more that are traditionally difficult to target using conventional small molecules. Recent development in targeted protein degradation opened a new opportunity to tackle this class of undruggable protein by directing them to the proteasome or lysosome, endogenous biological pathways for degrading selected protein. Lysosomal targeting chimera (LYTAC) is a technology developed in the Bertozzi Lab that engages extracellular or membrane protein to a cell surface lysosomal receptor, mannose-6-phosphate receptor (M6PR), for selected internalization and degradation of targeted protein in the lysosome. LYTAC is a bifunctional molecule that consists of a target-specific antibody that is modified with mannose-6-phosphonate (M6Pn), a bioisosteromer of the native ligand of M6PR, mannose-6-phosphate (M6P). Current synthesis of LYTAC involves either a lengthy chemical synthesis pathway that generate a heterogenous polymer of M6Pn or a solid-state peptide synthesis that generates a 2-mer or 5-mer of M6Pn, both of which are complex synthesis that is low yield and require extensive organic chemistry expertise and thus inaccessible to many biology and therapeutic-focused labs. We hereby developed an alternative synthetic strategy that uses a clickable monomer of M6Pn, which is now made commercially available, to construct LYTAC molecules via easily accessible chemistry. Our LYTAC synthesis is tunable and reproducible across experiments, and all reagents can be purchased commercially for easy access. We then demonstrated the protein of interest (POI) internalization and degradation activity of LYTAC across many mammalian cell lines, highlighting important factors that predict LYTAC efficiency across cell lines. This work provides a facile and scalable synthesis of a class of highly desirable molecule and robust assays to study the activity of LYTAC and POI degradation.
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