LYTACs that engage the asialoglycoprotein receptor for targeted protein degradation.
Green Ahn,Steven M. Banik,Caitlyn L. Miller,Nicholas M. Riley,Jennifer R. Cochran,Carolyn R. Bertozzi,Carolyn R. Bertozzi +6 more
TLDR
GalNAc-Lysosome-targeting chimeras (LYTACs) as discussed by the authors were developed to degrade extracellular and membrane proteins for degradation by bridging a target protein to the cation-independent mannose-6-phosphate receptor (CI-M6PR).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.read more
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Major advances in targeted protein degradation: PROTACs, LYTACs, and MADTACs.
Shanique B. Alabi,Craig M. Crews +1 more
TL;DR: Targeted protein degradation (TPD) as discussed by the authors is a novel and innovative chemical tool and therapeutic modality that facilitates complete removal of the protein molecules from within or outside the cell.
Journal ArticleDOI
Targeted protein degradation: mechanisms, strategies and application
TL;DR: In this article , the authors summarize recent advances of major targeted protein degradation (TPD) technologies, discuss their potential applications, and hope to provide a prime for both biologists and chemists who are interested in this vibrant field.
Journal ArticleDOI
Covalently Engineered Nanobody Chimeras for Targeted Membrane Protein Degradation.
Heng Zhang,Yu Han,Yuan-Fan Yang,Feng Lin,Kexin Li,Linghao Kong,Hongxiang Liu,Yongjun Dang,Jian Lin,Peng Chen +9 more
TL;DR: A covalent nanobody-based PROTAC strategy, termed GlueTAC, for targeted membrane protein degradation with high specificity and efficiency, and sustained eradication of tumor surface antigens both in vitro and in vivo.
Journal ArticleDOI
An expanded lexicon for the ubiquitin code
Ivan Dikic,Brenda A. Schulman +1 more
TL;DR: The ubiquitin code has greatly evolved from conventional E1, E2 and E3 enzymes that modify Lys residues on specific substrates to more complex processes that regulate and mediate ubiquitylation as mentioned in this paper .
Journal ArticleDOI
Protein degradation technology: a strategic paradigm shift in drug discovery
Haobin Li,Haobin Li,Jinyun Dong,Maohua Cai,Maohua Cai,Zhiyuan Xu,Xiang-Dong Cheng,Jiang-Jiang Qin,Jiang-Jiang Qin +8 more
TL;DR: In this paper, the authors summarized the development of protein degradation technologies in recent years and discussed their advantages, potential applications, and limitations, and shed light on the design, discovery, and clinical application of drugs associated with these degradation technologies.
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