Development of Cell‐Permeable, Non‐Helical Constrained Peptides to Target a Key Protein–Protein Interaction in Ovarian Cancer. (5th December 2016)

• Record Type: Journal Article
• Authors: Wiedmann, Mareike M.; Tan, Yaw Sing; Wu, Yuteng; Aibara, Shintaro; Xu, Wenshu; Sore, Hannah F.; Verma, Chandra S.; Itzhaki, Laura; Stewart, Murray; Brenton, James D.; Spring, David R.
• Is Part Of: Angewandte Chemie. Volume 129:Number 2(2017)
• Page Start: 539
• Page End: 544
• Publication Date: 2016-12-05
• Subjects: Konformativ festgelegte Peptide -- Peptidische Wirkstoffe -- Peptidmimetika -- Wirkstoffentwicklung -- Zellkern-Import; Chemistry -- Periodicals; 540
• DOI: 10.1002/ange.201609427
• Languages: English
• ISSNs: 0044-8249

Abstract

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.