Engineered coiled-coil HIF1α protein domain mimic
The development of targeted anti-cancer therapeutics offers the potential for increased efficacy of drugs and diagnostics. Utilizing modalities agnostic to tumor type, such as the hypoxic tumor microenvironment (TME), may assist in the development of universal tumor targeting agents. The hypoxia-ind...
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Published in | Biomaterials science Vol. 12; no. 11; pp. 2951 - 2959 |
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Main Authors | , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
England
Royal Society of Chemistry
28.05.2024
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Subjects | |
Online Access | Get full text |
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Summary: | The development of targeted anti-cancer therapeutics offers the potential for increased efficacy of drugs and diagnostics. Utilizing modalities agnostic to tumor type, such as the hypoxic tumor microenvironment (TME), may assist in the development of universal tumor targeting agents. The hypoxia-inducible factor (HIF), in particular HIF1, plays a key role in tumor adaptation to hypoxia, and inhibiting its interaction with p300 has been shown to provide therapeutic potential. Using a multivalent assembled protein (MAP) approach based on the self-assembly of the cartilage oligomeric matrix protein coiled-coil (COMPcc) domain fused to the critical residues of the C-terminal transactivation domain (C-TAD) of the α subunit of HIF1 (HIF1α), we generate HIF1α-MAP (H-MAP). The resulting H-MAP demonstrates picomolar binding affinity to p300, the ability to downregulate hypoxia-inducible genes, and
in vivo
tumor targeting capability.
Multivalent assembled proteins (MAPs) as protein domain mimics (PDMs) of HIF1α allows for improved tumor targeting. |
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Bibliography: | Electronic supplementary information (ESI) available: Figures of H-MAP and H-MAP-N biosynthesis, ELISA curves for HIF1α C-TAD and COMpcc to p300, luciferase activity of Luc-MDA-MB-231 in normoxic and hypoxic conditions after incubation of COMPcc, preliminary NIR fluorescence of tumors https://doi.org/10.1039/d4bm00354c after injection of COMPcc, H-MAP-N, or saline at 500 nM protein concentrations, NIR fluorescence in vivo ex vivo and measured total flux and radiance of tumors after injection of NIR-tagged COMPcc, H-MAP, and H-MAP-N, and tables for secondary structure compositions by CD and average mean area fluorescence for mouse organs after injection of H-MAP-N and COMPcc. See DOI ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 2047-4830 2047-4849 2047-4849 |
DOI: | 10.1039/d4bm00354c |