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Updated: Mar 10, 2026
Construction of Cyclic Cell-Penetrating Peptides for Enhanced Penetration of Biological Barriers
Published on: September 19, 2022
Development of Cell-Permeable, Non-Helical Constrained Peptides to Target a Key Protein-Protein Interaction in
Mareike M Wiedmann1,2, Yaw Sing Tan3, Yuteng Wu1
1Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK.
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.
Insights
Researchers developed new peptide inhibitors targeting hepatocyte nuclear factor 1-beta (HNF1β) to treat ovarian clear cell carcinoma (CCC). This approach offers a novel therapeutic strategy for a cancer with limited treatment options.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Ovarian clear cell carcinoma (CCC) presents limited therapeutic options and chemoresistance.
- Hepatocyte nuclear factor 1-beta (HNF1β) is overexpressed in CCC, making it a potential therapeutic target.
Purpose of the Study:
- To develop novel therapeutics for ovarian clear cell carcinoma by targeting HNF1β.
- To design and validate cell-permeable inhibitors of HNF1β nuclear import.
Main Methods:
- Validated HNF1β as a target via shRNA-mediated knockdown in CCC cell lines.
- Designed constrained proteomimetics targeting the HNF1β-importin α interaction using structural data and simulations.
- Developed peptide nuclear import inhibitors.
Main Results:
- Demonstrated the efficacy of targeting HNF1β in CCC models.
- Successfully designed the first series of constrained peptide nuclear import inhibitors.
- Showcased a generalizable approach for targeting transcription factor-protein interactions.
Conclusions:
- Targeting HNF1β with novel peptide inhibitors represents a promising therapeutic strategy for ovarian clear cell carcinoma.
- The developed inhibitors and approach may be applicable to other transcription factors.
- This research addresses the urgent need for new treatments for platinum-resistant ovarian cancer.
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