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.
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Posted 16 Mar, 2021
Posted 16 Mar, 2021
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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