Repository logo
 

Efficient development of stable and highly functionalised peptides targeting the CK2α/CK2β protein-protein interaction.

Accepted version
Peer-reviewed

No Thumbnail Available

Type

Article

Change log

Authors

Baker, David J 
Tan, Yaw Sing 
Atkinson, Eleanor L 

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.

Description

Keywords

0305 Organic Chemistry, 0601 Biochemistry and Cell Biology, Biomedical, Basic Science, 5.1 Pharmaceuticals

Journal Title

Chem Sci

Conference Name

Journal ISSN

2041-6520
2041-6539

Volume Title

10

Publisher

Royal Society of Chemistry (RSC)

Rights

All rights reserved
Sponsorship
Wellcome Trust (107714/Z/15/Z)
Engineering and Physical Sciences Research Council (EP/P020291/1)
Wellcome Trust (090340/Z/09/Z)