Dataset Information

Efficient development of stable and highly functionalised peptides targeting the CK2?/CK2? protein-protein interaction.

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.

SUBMITTER: Iegre J

PROVIDER: S-EPMC6530537 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Publications

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

Iegre Jessica J Brear Paul P Baker David J DJ Tan Yaw Sing YS Atkinson Eleanor L EL Sore Hannah F HF O' Donovan Daniel H DH Verma Chandra S CS Hyvönen Marko M Spring David R DR

Chemical science 20190412 19

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 <i>in vivo</i> 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 ...[more]

PMID: 31183056

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Project description:BACKGROUND:RNA-binding proteins (RBPs) are crucial in modulating RNA metabolism in eukaryotes thereby controlling an extensive network of RBP-RNA interactions. Although previous studies on the conservation of RBP targets have been carried out in lower eukaryotes such as yeast, relatively little is known about the extent of conservation of the binding sites of RBPs across mammalian species. RESULTS:In this study, we employ CLIP-seq datasets for 60 human RBPs and demonstrate that most binding sites for a third of these RBPs are conserved in at least 50% of the studied vertebrate species. Across the studied RBPs, binding sites were found to exhibit a median conservation of 58%, ~ 20% higher than random genomic locations, suggesting a significantly higher preservation of RBP-RNA interaction networks across vertebrates. RBP binding sites were highly conserved across primates with weak conservation profiles in birds and fishes. We also note that phylogenetic relationship between members of an RBP family does not explain the extent of conservation of their binding sites across species. Multivariate analysis to uncover features contributing to differences in the extents of conservation of binding sites across RBPs revealed RBP expression level and number of post-transcriptional targets to be the most prominent factors. Examination of the location of binding sites at the gene level confirmed that binding sites occurring on the 3' region of a gene are highly conserved across species with 90% of the RBPs exhibiting a significantly higher conservation of binding sites in 3' regions of a gene than those occurring in the 5'. Gene set enrichment analysis on the extent of conservation of binding sites to identify significantly associated human phenotypes revealed an enrichment for multiple developmental abnormalities. CONCLUSIONS:Our results suggest that binding sites of human RBPs are highly conserved across primates with weak conservation profiles in lower vertebrates and evolutionary relationship between members of an RBP family does not explain the extent of conservation of their binding sites. Expression level and number of targets of an RBP are important factors contributing to the differences in the extent of conservation of binding sites. RBP binding sites on 3' ends of a gene are the most conserved across species. Phenotypic analysis on the extent of conservation of binding sites revealed the importance of lineage-specific developmental events in post-transcriptional regulatory network evolution.

Dataset Information

Efficient development of stable and highly functionalised peptides targeting the CK2?/CK2? protein-protein interaction.

Publications

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

Similar Datasets

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