Development of Cell-Permeable, Non-Helical Constrained Peptides to Target a Key Protein-Protein Interaction in Ovarian Cancer
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- 作者：Mareike M. Wiedmann ; Dr. Yaw Sing Tan ; Yuteng Wu ; Dr. Shintaro Aibara ; Dr. Wenshu Xu ; Dr. Hannah F. Sore ; Dr. Chandra S. Verma ; Dr. Laura Itzhaki ; Dr. Murray Stewart ; Dr. James D. Brenton and Prof. David R. Spring
- 刊名：Angewandte Chemie International Edition
- 出版年：2017
- 出版时间：January 9, 2017
- 年：2017
- 卷：56
- 期：2
- 页码：524-529
- 全文大小：3237K
- ISSN：1521-3773
文摘
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.