Development of Cell-Permeable, Non-Helical Constrained Peptides to Target a Key Protein-Protein Interaction in Ovarian Cancer
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Wiedmann, M., Tan, Y., Wu, Y., Aibara, S., Xu, W., Sore, H., Verma, C., et al. (2017). Development of Cell-Permeable, Non-Helical Constrained Peptides to Target a Key Protein-Protein Interaction in Ovarian Cancer. Angewandte Chemie, 129 (2), 539-544. https://doi.org/10.1002/ange.201609427
There is a lack of current treatment options for ovarian clear cell carcinoma (CCC) and the cancer is often resistant to platinum-based chemotherapy. Hence there is an urgent need for novel therapeutics. The transcription factor hepatocyte nuclear factor 1β (HNF1β) is ubiquitously overexpressed in CCC and is seen as an attractive therapeutic target. This was validated through shRNA-mediated knockdown of the target protein, HNF1β, in five high- and low-HNF1β-expressing CCC lines. To inhibit the protein function, cell-permeable, non-helical constrained proteomimetics to target the HNF1β–importin α protein–protein interaction were designed, guided by X-ray crystallographic data and molecular dynamics simulations. In this way, we developed the first reported series of constrained peptide nuclear import inhibitors. Importantly, this general approach may be extended to other transcription factors.
Konformativ festgelegte Peptide, Peptidische Wirkstoffe, Peptidmimetika, Wirkstoffentwicklung, Zellkern-Import
M.W. is funded by Cancer Research UK, Department of Chemistry at the University of Cambridge, School of the Physical Sciences and the Cambridge Cancer Centre. The Spring lab acknowledges support from the European Research Council under the European Union's Seventh Framework Programme (FP7/2007-2013)/ERC grant agreement no [279337/DOS]. D.R.S acknowledges support from a Royal Society Wolfson Research Merit award. In addition, the group research was supported by grants from the Engineering and Physical Sciences Research Council, Biotechnology and Biological Sciences Research Council, Medical Research Council, Royal Society and Welcome Trust. Funding in part was also provided by Medical Research Council Grant U105178939 to M.S.
European Research Council (279337)
Engineering and Physical Sciences Research Council (EP/K039520/1)
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External DOI: https://doi.org/10.1002/ange.201609427
This record's URL: https://www.repository.cam.ac.uk/handle/1810/262091
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