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LYTAC

LYTAC (Lysosome-targeting chimaeras) is a promising strategy that targeted degradation of interested proteins through lysosomal degradation pathway, such as EGFR degradation pathway. In comparison to PROTAC method, LYTAC can target extracellular and membrane-associated proteins using conjugates that bind both a cell-surface lysosome-shuttling receptor and the extracellular domain.

LYTAC system is based on the lysosome-targeting receptors (LTRs), LTRs mediate the transport of proteins to lysosomes and subsequent degradation. LYTAC consists with a specific antibody bound to transmembrane proteins or extracellular proteins and a short peptide modified with mannose-6-phosphate (M6P). The former can specifically bind to the target protein to be degraded; and the latter ensure that the target protein can enter the lysosome along with the LTR to complete the degradation. When M6P binding to cation-independent mannose-6-phosphate receptor (CI-M6PR) and the LYTAC complex with target protein is engulfed by the cell membrane and formed a transport vesicle, then the transport vesicle is carried into the lysosome, resulting in the degradation of the target protein.

The concept of LYTACsFigure 1 The concept of LYTACs.

A: A glycopolypeptide ligand for CI-M6PR is conjugated to an antibody to traffic secreted and membrane-associated proteins to lysosomes. B: Synthesis of M6Pn glycopolypeptide ligands for CI-M6PR. bpy, bipyridyl; COD, cyclooctadiene; RT, room temperature; THF, tetrahydrofuran; TMS, trimethylsilyl. C: Assay for the internalization of NA-647 by biotin-based LYTACs.

LYTAC has a universality for different proteins degradation research. It had been reported that M6P and M6Pn can effectively carry the cargo into the cell and localize to the lysosome. At present, there are many reported molecules that can be used in LYTAC design. Such as molecule-Ab-2, which can effectively degrade the EGFR relying on IGFR2 without off-target effects. And molecule-Ab-3 and Atz-M6Pn can degrade PD-L1 molecule by using anti-PD-L1 antibody and PD-L1 antibody atezolizumab.

As a professional biotechnology service company, Profacgen has been paying close attention to the development of LYTACs, and we welcome in-depth discussions with you on the application and design of this technology. Please feel free to contact us for more information.

Reference

  1. Banik, S. M., Pedram, K., Wisnovsky, S., Ahn, G., Riley, N. M., Bertozzi, C. R. (2020). Lysosome-targeting chimaeras for degradation of extracellular proteins. Nature. doi:10.1038/s41586-020-2545-9

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