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Development of Cell-Permeable, Non-Helical Constrained Peptides to Target a Key Protein-Protein Interaction in Ovarian Cancer
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab). Cambridge Biomedical Campus, UK.ORCID iD: 0000-0003-2221-482X
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Number of Authors: 112017 (English)In: Angewandte Chemie International Edition, ISSN 1433-7851, E-ISSN 1521-3773, Vol. 56, no 2, p. 524-529Article in journal (Refereed) Published
Abstract [en]

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 1 beta (HNF1 beta) is ubiquitously overexpressed in CCC and is seen as an attractive therapeutic target. This was validated through shRNA-mediated knockdown of the target protein, HNF1 beta, in five high-and low-HNF1 beta-expressing CCC lines. To inhibit the protein function, cellpermeable, non-helical constrained proteomimetics to target the HNF1 beta-importin a 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.

Place, publisher, year, edition, pages
2017. Vol. 56, no 2, p. 524-529
Keywords [en]
constrained peptides, drug discovery, nuclear import, peptide therapeutics, peptidomimetics
National Category
Chemical Sciences
Identifiers
URN: urn:nbn:se:su:diva-141397DOI: 10.1002/anie.201609427ISI: 000394996100012PubMedID: 27918136OAI: oai:DiVA.org:su-141397DiVA, id: diva2:1091198
Available from: 2017-04-26 Created: 2017-04-26 Last updated: 2022-03-23Bibliographically approved

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Aibara, Shintaro

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