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Development of Cell-Permeable, Non-Helical Constrained Peptides to Target a Key Protein-Protein Interaction in Ovarian Cancer

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cam.issuedOnline2016-12-05
cam.orpheus.successThu Jan 30 10:20:25 GMT 2020 - The item has an open VoR version.
dc.contributor.authorWiedmann, MM
dc.contributor.authorTan, YS
dc.contributor.authorWu, Y
dc.contributor.authorAibara, S
dc.contributor.authorXu, W
dc.contributor.authorSore, HF
dc.contributor.authorVerma, CS
dc.contributor.authorItzhaki, L
dc.contributor.authorStewart, M
dc.contributor.authorBrenton, JD
dc.contributor.authorSpring, DR
dc.contributor.orcidSore, Hannah [0000-0002-6542-0394]
dc.contributor.orcidItzhaki, Laura [0000-0001-6504-2576]
dc.contributor.orcidBrenton, James [0000-0002-5738-6683]
dc.contributor.orcidSpring, David [0000-0001-7355-2824]
dc.date.accessioned2017-01-27T15:16:57Z
dc.date.available2017-01-27T15:16:57Z
dc.date.issued2017-01-09
dc.description.abstractThere 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.
dc.description.sponsorshipM.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.
dc.identifier.doi10.17863/CAM.7339
dc.identifier.eissn1521-3757
dc.identifier.issn0044-8249
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/262091
dc.language.isoeng
dc.publisherWiley
dc.publisher.urlhttp://dx.doi.org/10.1002/ange.201609427
dc.rightsAttribution 4.0 International
dc.rightsAttribution 4.0 International
dc.rightsAttribution 4.0 International
dc.rightsAttribution 4.0 International
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectKonformativ festgelegte Peptide
dc.subjectPeptidische Wirkstoffe
dc.subjectPeptidmimetika
dc.subjectWirkstoffentwicklung
dc.subjectZellkern-Import
dc.titleDevelopment of Cell-Permeable, Non-Helical Constrained Peptides to Target a Key Protein-Protein Interaction in Ovarian Cancer
dc.typeArticle
dcterms.dateAccepted2016-11-02
prism.endingPage544
prism.issueIdentifier2
prism.publicationDate2017
prism.publicationNameAngewandte Chemie
prism.startingPage539
prism.volume129
pubs.funder-project-idEuropean Research Council (279337)
pubs.funder-project-idEngineering and Physical Sciences Research Council (EP/K039520/1)
rioxxterms.licenseref.startdate2017-01-09
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by/4.0/
rioxxterms.typeJournal Article/Review
rioxxterms.versionVoR
rioxxterms.versionofrecord10.1002/ange.201609427

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