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Article
Peng Chen
Peking University
Corresponding Author
ORCiD: https://orcid.org/0000-0002-0402-7417
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Targeted degradation of membrane proteins would afford an attractive and general strategy for treating various diseases that remain difficult with the current 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 designed a MS-based screening platform for rapid development of covalent nanobody (Gluebody) that allowed proximity-enabled ligation with surface antigens on cancer cells. By conjugation with the cell-penetrating peptide and lysosomal-sorting sequence, the resulting GlueTAC chimera exhibited enhanced internalization with high efficacy and sustained eradication of tumor surface antigens such as PD-L1 and EGFR both in vitro and in vivo, which has broad applications in biomedical research and therapeutics.
Keywords
PROTAC, membrane proteins, therapeutics, biomedical research
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This is a preprint. It has not completed peer review.
Article
Peng Chen
Peking University
Corresponding Author
ORCiD: https://orcid.org/0000-0002-0402-7417
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
History
CURRENT STATUS: Posted
Version 1
Posted 16 Mar, 2021
No community comments so far
License:
This work is licensed under a CC BY 4.0 License. Read Full License
Targeted degradation of membrane proteins would afford an attractive and general strategy for treating various diseases that remain difficult with the current 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 designed a MS-based screening platform for rapid development of covalent nanobody (Gluebody) that allowed proximity-enabled ligation with surface antigens on cancer cells. By conjugation with the cell-penetrating peptide and lysosomal-sorting sequence, the resulting GlueTAC chimera exhibited enhanced internalization with high efficacy and sustained eradication of tumor surface antigens such as PD-L1 and EGFR both in vitro and in vivo, which has broad applications in biomedical research and therapeutics.
Figure 1
Figure 2
Figure 3
This preprint is available for download as a PDF.
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