期刊
NATURE CHEMICAL BIOLOGY
卷 17, 期 9, 页码 937-946出版社
NATURE PORTFOLIO
DOI: 10.1038/s41589-021-00770-1
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资金
- National Institutes of Health [R01GM058867, K00CA21245403]
- St. Baldrick's/Stand Up 2 Cancer Pediatric Dream Team Translational Cancer Research Grant
- National Science Foundation Graduate Research Fellowship
- National Institute of General Medical Sciences
Selective protein degradation platforms such as LYTACs provide new opportunities for therapeutic development and biological research. By targeting specific lysosome receptors in a cell-type-specific manner, these LYTACs can efficiently degrade extracellular proteins and hold promise for cell-type-restricted protein degradation strategies.
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-GaINAc) motif that engages ASGPR to drive the downregulation of proteins. Degradation of epidermal growth factor receptor (EGFR) by GaINAc-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-GaINAc ligand degrades integrins and reduces cancer cell proliferation. Degradation with a single tri-GaINAc ligand prompted site-specific conjugation on antibody scaffolds, which improved the pharmacokinetic profile of GaINAc-LYTACs in vivo. GaINAc-LYTACs thus represent an avenue for cell-type-restricted protein degradation.
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