Development of Cell-Permeable, Non-Helical Constrained Peptides to Target a Key Protein-Protein Interaction in Ovarian Cancer.
Verma, Chandra S
Angewandte Chemie (International ed. in English)
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Wiedmann, M. M., Tan, Y. S., Wu, Y., Aibara, S., Xu, W., Sore, H., Verma, C. S., et al. (2017). Development of Cell-Permeable, Non-Helical Constrained Peptides to Target a Key Protein-Protein Interaction in Ovarian Cancer.. Angewandte Chemie (International ed. in English), 56 (2), 524-529. https://doi.org/10.1002/anie.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.
Humans, Ovarian Neoplasms, Crystallography, X-Ray, Molecular Structure, Protein Binding, Models, Molecular, Female, Molecular Dynamics Simulation, Cell-Penetrating Peptides
Royal Society (WM150022)
European Research Council (279337)
MRC (MC_PC_14116 v2)
External DOI: https://doi.org/10.1002/anie.201609427
This record's URL: https://www.repository.cam.ac.uk/handle/1810/268507
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