Статья

Covalently Engineered Nanobody Chimeras for Targeted Membrane Protein Degradation

Heng ZhangShenzhen Bay Laboratory, Shenzhen 518055, ChinaYu HanSynthetic and Functional Biomolecules Center, Beijing National Laboratory for Molecular Sciences, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, ChinaYuanfan YangSynthetic and Functional Biomolecules Center, Beijing National Laboratory for Molecular Sciences, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, ChinaFeng LinPeking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, ChinaKexin LiPeking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, ChinaLinghao KongPeking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, ChinaHongxiang LiuShenzhen Bay Laboratory, Shenzhen 518055, ChinaYongjun DangCenter for Novel Target and Therapeutic Intervention, Institute of Life Sciences, Chongqing Medical University, Chongqing 400016, ChinaJian LinSynthetic and Functional Biomolecules Center, Beijing National Laboratory for Molecular Sciences, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, ChinaPeng R. ChenKey Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, Peking University, Beijing 100871, China

2021en

ABI

Аннотация

The targeted degradation of membrane proteins would afford an attractive and general strategy for treating various diseases that remain difficult with the current proteolysis-targeting chimera (PROTAC) methodology. We herein report a covalent nanobody-based PROTAC strategy, termed GlueTAC, for targeted membrane protein degradation with high specificity and efficiency. We first established a mass-spectrometry-based screening platform for the rapid development of a covalent nanobody (GlueBody) that allowed proximity-enabled cross-linking with surface antigens on cancer cells. By conjugation with a cell-penetrating peptide and a lysosomal-sorting sequence, the resulting GlueTAC chimera triggered the internalization and degradation of programmed death-ligand 1 (PD-L1), which provides a new avenue to target and degrade cell-surface proteins.

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Идентификаторы

DOI: 10.1021/jacs.1c08521

Цитирования и источники

Цитирований: 2Использованных источников: 0

Показатели — AkademScholar