Efficient development of stable and highly functionalised peptides targeting the CK2α/CK2β protein–protein interaction†

Efficient development of stable and highly functionalised peptides targeting the CK2α/CK2β protein–protein interaction†
Title:
Efficient development of stable and highly functionalised peptides targeting the CK2α/CK2β protein–protein interaction†
Other Titles:
Chemical Science
Keywords:
Publication Date:
09 April 2019
Citation:
Chem. Sci., 2019,10, 5056-5063
Abstract:
The discovery of new Protein–Protein Interaction (PPI) modulators is currently limited by the difficulties associated with the design and synthesis of selective small molecule inhibitors. Peptides are a potential solution for disrupting PPIs; however, they typically suffer from poor stability in vivo and limited tissue penetration hampering their wide spread use as new chemical biology tools and potential therapeutics. In this work, a combination of CuAAC chemistry, molecular modelling, X-ray crystallography, and biological validation allowed us to develop highly functionalised peptide PPI inhibitors of the protein CK2. The lead peptide, CAM7117, prevents the formation of the holoenzyme assembly in vitro, slows down proliferation, induces apoptosis in cancer cells and is stable in human serum. CAM7117 could aid the development of novel CK2 inhibitors acting at the interface and help to fully understand the intracellular pathways involving CK2. Importantly, the approach adopted herein could be applied to many PPI targets and has the potential to ease the study of PPIs by efficiently providing access to functionalised peptides.
License type:
http://creativecommons.org/licenses/by/4.0/
Funding Info:
This work was funded by the European Research Council under the European Union's Seventh Framework Programme (FP7/2007-2013)/ERC and the Wellcome Trust Strategic (090340/Z/09/Z) Award (to DRS and MH). In addition, the group research was supported by grants from the Engineering and Physical Sciences Research Council, Biotechnology and Biological Sciences Research Council, Medical Research Council and Royal Society. JI would like to thank Trinity College, University of Cambridge for funding. YST and CSV would like to thank A*STAR (IAF-PP H17/01/a0/010) for support. We would like to thank Diamond Light Source for access to and support at beamline iO4 (proposal 18548) and the Department of Biochemistry X-ray crystallographic and Biophysics facilities for access to instrumentation.
Description:
ISSN:
2041-6520
2041-6539
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