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Lysosome Targeting Chimeras (LYTACs) for the Degradation of Secreted and Membrane Proteins by Banik, Steven ;Pedram, Kayvon ;Wisnovsky, Simon ;Riley, Nicholas ;Bertozzi, Carolyn is a scholarly article available to read on EtoBox.

What is Lysosome Targeting Chimeras (LYTACs) for the Degradation of Secreted and Membrane Proteins about?

Targeted protein degradation is a powerful strategy to address the canonically undruggable proteome. However, current technologies are limited to targets with cytosolically-accessible and ligandable domains. Here, we designed and synthesized conjugates capable of binding both a cell surface lysosome targeting receptor and the extracellular domain of a target protein. These lysosome targeting chimeras (LYTACs) consist of an antibody fused to agonist glycopeptide ligands for the cation-independent mannose-6-phosphate receptor (CI-M6PR). LYTACs enabled a CRISPRi knockdown screen revealing the biochemical pathway for CI-M6PR-mediated cargo internalization. We demonstrated that LYTACs mediate efficient degradation of Apolipoprotein-E4, epidermal growth factor receptor (EGFR), CD71, and programmed death-ligand 1 (PD-L1). LYTACs represent a modular strategy for directing secreted and membrane proteins for degradation in the context of both basic research and therapy.

Author

Banik, Steven ;Pedram, Kayvon ;Wisnovsky, Simon ;Riley, Nicholas ;Bertozzi, Carolyn

Publisher

American Chemical Society (ACS)

Published

2019

Language

EN