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

Published version
Peer-reviewed

Type

Article

Change log

Authors

Wiedmann, Mareike M  ORCID logo  https://orcid.org/0000-0002-4728-7155
Wu, Yuteng 
Xu, Wenshu 

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.

Description

Keywords

constrained peptides, drug discovery, nuclear import, peptide therapeutics, peptidomimetics, Cell-Penetrating Peptides, Crystallography, X-Ray, Female, Humans, Models, Molecular, Molecular Dynamics Simulation, Molecular Structure, Ovarian Neoplasms, Protein Binding

Journal Title

Angew Chem Int Ed Engl

Conference Name

Journal ISSN

1433-7851
1521-3773

Volume Title

56

Publisher

Wiley
Sponsorship
Engineering and Physical Sciences Research Council (EP/J016012/1)
Royal Society (WM150022)
European Research Council (279337)
Medical Research Council (G1002329)
Engineering and Physical Sciences Research Council (EP/K039520/1)
Engineering and Physical Sciences Research Council (EP/P020291/1)
MRC (MC_PC_14116 v2)