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Lysosome Targeting Chimeras (LYTACs) for the Degradation of Secreted and Membrane Proteins

preprint
revised on 11.11.2019, 21:13 and posted on 20.11.2019, 12:05 by Steven Banik, Kayvon Pedram, Simon Wisnovsky, Nicholas Riley, Carolyn Bertozzi

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.

Funding

NIH R01CA227942

History

Email Address of Submitting Author

bertozzi@stanford.edu

Institution

Stanford University

Country

United States

ORCID For Submitting Author

0000-0003-4482-2754

Declaration of Conflict of Interest

A patent application relating to lysosome targeting chimeras has been filed by Stanford University (docket number STAN-1497PRV). C.R.B. is a co-founder and Scientific Advisory Board member of Palleon Pharmaceuticals, Enable Bioscience, Redwood Biosciences (a subsidiary of Catalent) and InterVenn Biosciences, and a member of the Board of Directors of Eli Lilly & Company.

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