Cell-penetrating Alphabody protein scaffolds for intracellular drug targeting
- Author
- Erwin Pannecoucke (UGent) , Maaike Van Trimpont (UGent) , Johan Desmet, Tim Pieters (UGent) , Lindy Reunes (UGent) , Lisa Demoen (UGent) , Marnik Vuylsteke, Stefan Loverix, Karen Vandenbroucke, Philippe Alard, Paula Henderikx, Sabrina Deroo, Franky Baatz, Eric Lorent, Sophie Thiolloy, Klaartje Somers, Yvonne McGrath, Pieter Van Vlierberghe (UGent) , Ignace Lasters and Savvas Savvides (UGent)
- Organization
- Project
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- Intracellulaire therapeutische alphabodies
- Towards the structural and molecular basis of pro-inflammatory signalling assemblies mediated by IL-23 and IL-12
- The molecular and structural basis of pro- and anti-inflammatory signalling assemblies mediated by IL-27 and IL-35.
- ERC Professorship: EPITALL
- Moleculaire en structurele studie van standaard en pathologische FLT3 receptor activatie
- Abstract
- The therapeutic scope of antibody and nonantibody protein scaffolds is still prohibitively limited against intracellular drug targets. Here, we demonstrate that the Alphabody scaffold can be engineered into a cell-penetrating protein antagonist against induced myeloid leukemia cell differentiation protein MCL-1, an intracellular target in cancer, by grafting the critical B-cell lymphoma 2 homology 3 helix of MCL-1 onto the Alphabody and tagging the scaffold’s termini with designed cell-penetration polypeptides. Introduction of an albumin-binding moiety extended the serum half-life of the engineered Alphabody to therapeutically relevant levels, and administration thereof in mouse tumor xenografts based on myeloma cell lines reduced tumor burden. Crystal structures of such a designed Alphabody in complex with MCL-1 and serum albumin provided the structural blueprint of the applied design principles. Collectively, we provide proof of concept for the use of Alphabodies against intracellular disease mediators, which, to date, have remained in the realm of small-molecule therapeutics.
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Citation
Please use this url to cite or link to this publication: http://hdl.handle.net/1854/LU-8704185
- MLA
- Pannecoucke, Erwin, et al. “Cell-Penetrating Alphabody Protein Scaffolds for Intracellular Drug Targeting.” SCIENCE ADVANCES, vol. 7, no. 13, 2021, doi:10.1126/sciadv.abe1682.
- APA
- Pannecoucke, E., Van Trimpont, M., Desmet, J., Pieters, T., Reunes, L., Demoen, L., … Savvides, S. (2021). Cell-penetrating Alphabody protein scaffolds for intracellular drug targeting. SCIENCE ADVANCES, 7(13). https://doi.org/10.1126/sciadv.abe1682
- Chicago author-date
- Pannecoucke, Erwin, Maaike Van Trimpont, Johan Desmet, Tim Pieters, Lindy Reunes, Lisa Demoen, Marnik Vuylsteke, et al. 2021. “Cell-Penetrating Alphabody Protein Scaffolds for Intracellular Drug Targeting.” SCIENCE ADVANCES 7 (13). https://doi.org/10.1126/sciadv.abe1682.
- Chicago author-date (all authors)
- Pannecoucke, Erwin, Maaike Van Trimpont, Johan Desmet, Tim Pieters, Lindy Reunes, Lisa Demoen, Marnik Vuylsteke, Stefan Loverix, Karen Vandenbroucke, Philippe Alard, Paula Henderikx, Sabrina Deroo, Franky Baatz, Eric Lorent, Sophie Thiolloy, Klaartje Somers, Yvonne McGrath, Pieter Van Vlierberghe, Ignace Lasters, and Savvas Savvides. 2021. “Cell-Penetrating Alphabody Protein Scaffolds for Intracellular Drug Targeting.” SCIENCE ADVANCES 7 (13). doi:10.1126/sciadv.abe1682.
- Vancouver
- 1.Pannecoucke E, Van Trimpont M, Desmet J, Pieters T, Reunes L, Demoen L, et al. Cell-penetrating Alphabody protein scaffolds for intracellular drug targeting. SCIENCE ADVANCES. 2021;7(13).
- IEEE
- [1]E. Pannecoucke et al., “Cell-penetrating Alphabody protein scaffolds for intracellular drug targeting,” SCIENCE ADVANCES, vol. 7, no. 13, 2021.
@article{8704185,
abstract = {{The therapeutic scope of antibody and nonantibody protein scaffolds is still prohibitively limited against intracellular drug targets. Here, we demonstrate that the Alphabody scaffold can be engineered into a cell-penetrating protein antagonist against induced myeloid leukemia cell differentiation protein MCL-1, an intracellular target in cancer, by grafting the critical B-cell lymphoma 2 homology 3 helix of MCL-1 onto the Alphabody and tagging the scaffold’s termini with designed cell-penetration polypeptides. Introduction of an albumin-binding moiety extended the serum half-life of the engineered Alphabody to therapeutically relevant levels, and administration thereof in mouse tumor xenografts based on myeloma cell lines reduced tumor burden. Crystal structures of such a designed Alphabody in complex with MCL-1 and serum albumin provided the structural blueprint of the applied design principles. Collectively, we provide proof of concept for the use of Alphabodies against intracellular disease mediators, which, to date, have remained in the realm of small-molecule therapeutics.}},
articleno = {{eabe1682}},
author = {{Pannecoucke, Erwin and Van Trimpont, Maaike and Desmet, Johan and Pieters, Tim and Reunes, Lindy and Demoen, Lisa and Vuylsteke, Marnik and Loverix, Stefan and Vandenbroucke, Karen and Alard, Philippe and Henderikx, Paula and Deroo, Sabrina and Baatz, Franky and Lorent, Eric and Thiolloy, Sophie and Somers, Klaartje and McGrath, Yvonne and Van Vlierberghe, Pieter and Lasters, Ignace and Savvides, Savvas}},
issn = {{2375-2548}},
journal = {{SCIENCE ADVANCES}},
language = {{eng}},
number = {{13}},
pages = {{17}},
title = {{Cell-penetrating Alphabody protein scaffolds for intracellular drug targeting}},
url = {{http://dx.doi.org/10.1126/sciadv.abe1682}},
volume = {{7}},
year = {{2021}},
}
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