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LYTACs that engage the asialoglycoprotein receptor for targeted protein degradation

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Ahn, Green, Banik, Steven M., Miller, Caitlyn L., Riley, Nicholas M., Cochran, Jennifer R., Bertozzi, Carolyn R.·2021·Nature Chemical Biology
DOI 10.1038/s41589-021-00770-1

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Abstract

Selective protein degradation platforms have afforded new development opportunities for therapeutics and tools for biological inquiry. The first lysosome-targeting chimeras (LYTACs) targeted extracellular and membrane proteins for degradation by bridging a target protein to the cation-independent mannose-6-phosphate receptor (CI-M6PR). Here, we developed LYTACs that engage the asialoglycoprotein receptor (ASGPR), a liver-specific lysosome-targeting receptor, to degrade extracellular proteins in a cell-type-specific manner. We conjugated binders to a triantenerrary N-acetylgalactosamine (tri-GalNAc) motif that engages ASGPR to drive the downregulation of proteins. Degradation of epidermal growth factor receptor (EGFR) by GalNAc-LYTAC attenuated EGFR signaling compared to inhibition with an antibody. Furthermore, we demonstrated that a LYTAC consisting of a 3.4-kDa peptide binder linked to a tri-GalNAc ligand degrades integrins and reduces cancer cell proliferation. Degradation with a single tri-GalNAc ligand prompted site-specific conjugation on antibody scaffolds, which improved the pharmacokinetic profile of GalNAc-LYTACs in vivo. GalNAc-LYTACs thus represent an avenue for cell-type-restricted protein degradation. Lysosome-targeting chimeras (LYTACs) based on glycan ligands of the asialoglycoprotein receptor facilitate the cell-specific targeting and turnover of proteins by lysosomal enzymes, expanding the scope of LYTAC-mediated targeted protein degradation.

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Metadata

Authors
Ahn, G., Banik, S. M., Miller, C. L., Riley, N. M., Cochran, J. R., & Bertozzi, C. R.
Venue
Nature Chemical Biology
Publisher
Springer Science and Business Media LLC
Published
2021-03-25
Volume
17
Issue
9
Pages
937-946
ISSN
  • 1552-4450 (ISSN-L)
  • 1552-4469
DOI
10.1038/s41589-021-00770-1
OpenAlex
W3136546688
Cited by
619
References
17
FWCI
21.47
Type
journal article
Language
en
Open access
green
Licence
Funders
  • National Science Foundation Graduate Research Fellowship
  • National Institute of General Medical Sciences F32 Postdoctoral Fellowship
  • U.S. Department of Health & Human Services | National Institutes of Health (K00CA21245403)
  • St. Baldrick’s / Stand Up 2 Cancer Pediatric Dream Team Translational Cancer Research Grant
  • U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (R01GM058867)

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CoChat. (2026). Citation check: LYTACs that engage the asialoglycoprotein receptor for targeted protein degradation. https://app.cochat.ai/papers/10.1038/s41589-021-00770-1
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Ahn, G., Banik, S. M., Miller, C. L., Riley, N. M., Cochran, J. R., & Bertozzi, C. R. (2021). LYTACs that engage the asialoglycoprotein receptor for targeted protein degradation. Nature Chemical Biology. https://doi.org/10.1038/s41589-021-00770-1

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