title: Development of Cell-Permeable, Non-Helical Constrained Peptides to Target a Key Protein-Protein Interaction in Ovarian Cancer.
abstract: 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.
authors.affiliation: Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK.|Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge, CB2 0RE, UK.
authors.forename: Mareike M
authors.identifier: 0000-0002-4728-7155
authors.initials: MM
authors.lastname: Wiedmann
authors.affiliation: Bioinformatics Institute, Agency for Science, Technology and Research, A*STAR, 30 Biopolis Street, #07-01 Matrix, Singapore, 138671, Singapore.
authors.forename: Yaw Sing
authors.identifier: 0000-0002-2522-9421
authors.initials: YS
authors.lastname: Tan
authors.affiliation: Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK.
authors.forename: Yuteng
authors.initials: Y
authors.lastname: Wu
authors.affiliation: SciLifeLab, Tomtebodavägen 23A, 171 65 Solna, Stockholm, Sweden.|MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge, CB2 0QH, UK.
authors.forename: Shintaro
authors.identifier: 0000-0003-2221-482X
authors.initials: S
authors.lastname: Aibara
authors.affiliation: Department of Pharmacology, Tennis Court Road, Cambridge, CB2 1PD, UK.
authors.forename: Wenshu
authors.initials: W
authors.lastname: Xu
authors.affiliation: Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK.
authors.forename: Hannah F
authors.identifier: 0000-0002-6542-0394
authors.initials: HF
authors.lastname: Sore
authors.affiliation: Bioinformatics Institute, Agency for Science, Technology and Research, A*STAR, 30 Biopolis Street, #07-01 Matrix, Singapore, 138671, Singapore.|School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore, 637551, Singapore.|Department of Biological Sciences, National University of Singapore, 14 Science Drive 4, Singapore, 117543, Singapore.
authors.forename: Chandra S
authors.initials: CS
authors.lastname: Verma
authors.affiliation: Department of Pharmacology, Tennis Court Road, Cambridge, CB2 1PD, UK.
authors.forename: Laura
authors.identifier: 0000-0001-6504-2576
authors.initials: L
authors.lastname: Itzhaki
authors.affiliation: MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge, CB2 0QH, UK.
authors.forename: Murray
authors.initials: M
authors.lastname: Stewart
authors.affiliation: Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge, CB2 0RE, UK.
authors.forename: James D
authors.identifier: 0000-0002-5738-6683
authors.initials: JD
authors.lastname: Brenton
authors.affiliation: Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK.
authors.forename: David R
authors.identifier: 0000-0001-7355-2824
authors.initials: DR
authors.lastname: Spring
mesh_terms: D057846:Cell-Penetrating Peptides / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D005260:Female; D006801:Humans; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D010051:Ovarian Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects
chemical_list: D057846:Cell-Penetrating Peptides
keywords: constrained peptides; drug discovery; nuclear import; peptide therapeutics; peptidomimetics