Development of Triantennary N-Acetylgalactosamine Conjugates as Degraders for Extracellular Proteins
TLDR
In this article, the authors exploited the potential of the asialoglycoprotein receptor (ASGPR), a lysosomal targeting receptor specifically expressed on liver cells, for the degradation of extracellular proteins including membrane proteins.Abstract:
Targeted protein degradation (TPD) technology has drawn significant attention from researchers in both academia and industry. It is rapidly evolved as a new therapeutic modality and also a useful chemical tool in selectively depleting various protein targets. As most efforts focus on cytosolic proteins using PROteolysis TArgeting Chimera (PROTAC), LYsosome TArgeting Chimera (LYTAC) recently emerged as a promising technology to deliver extracellular protein targets to lysosome for degradation through the cation-independent mannose-6-phosphate receptor (CI-M6PR). In this study, we exploited the potential of the asialoglycoprotein receptor (ASGPR), a lysosomal targeting receptor specifically expressed on liver cells, for the degradation of extracellular proteins including membrane proteins. The ligand of ASGPR, triantennary N-acetylgalactosamine (tri-GalNAc), was conjugated to biotin, antibodies, or fragments of antibodies to generate a new class of degraders. We demonstrated that the extracellular protein targets could be successfully internalized and delivered into lysosome for degradation in liver cell lines specifically by these degraders. This work will add a new dimension to TPD with cell type specificity.read more
Citations
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Journal ArticleDOI
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
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
Bifunctional small molecules that mediate the degradation of extracellular proteins.
David Caianiello,Mengwen Zhang,Jason Ray,Rebecca Howell,Jake C Swartzel,Emily M J Branham,Egor Chirkin,Venkata R. Sabbasani,Angela Z Gong,David M McDonald,Viswanathan Muthusamy,David Spiegel +11 more
TL;DR: In this article, the authors developed a class of modular, bifunctional synthetic molecules called MoDE-As (molecular degraders of extracellular proteins through the asialoglycoprotein receptor (ASGPR)), which mediate the degradation of extacellular proteins.
Journal ArticleDOI
Proteolysis-targeting chimera (PROTAC) delivery system: advancing protein degraders towards clinical translation.
TL;DR: The latest progress in improving the in vivo degradation efficacy of PROTACs through delivery strategies is surveyed, design principles for PROTAC-based delivery systems are outlined, and the future opportunities in this field are outlooked.
Journal ArticleDOI
Emerging protein degradation strategies: expanding the scope to extracellular and membrane proteins.
Jiayi Lin,Jinmei Jin,Yi-Wen Shen,Li-Jun Zhang,Gang Gong,Huiting Bian,Hong-Zhuan Chen,Dale G. Nagle,Ye Wu,Weidong Zhang,Weidong Zhang,Xin Luan +11 more
Abstract: Classic small molecule inhibitors that directly target pathogenic proteins typically rely on the accessible binding sites to achieve prolonged occupancy and influence protein functions. The emerging targeted protein degradation (TPD) strategies exemplified by PROteolysis TArgeting Chimeras (PROTACs) are revolutionizing conventional drug discovery modality to target proteins of interest (POIs) that were categorized as "undruggable" before, however, these strategies are limited within intracellular POIs. The novel new degrader technologies such as LYsosome-TArgeting Chimaeras (LYTACs) and Antibody-based PROTACs (AbTACs) have been successfully developed to expand the scope of TPD to extracellular and membrane proteins, fulfilling huge unmet medical needs. Here, we systematically review the currently viable protein degradation strategies, emphasize that LYTACs and AbTACs turn a new avenue for the development of TPD, and highlight the potential challenges and directions in this vibrant field.
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