Efficient development of stable and highly functionalised peptides targeting the CK2α/CK2β protein–protein interaction
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 viv...
| Main Authors: | , , , , , , , , , |
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| Format: | Journal Article |
| Language: | English |
| Published: |
2019
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| Online Access: | https://hdl.handle.net/10356/106361 http://hdl.handle.net/10220/49635 |
| _version_ | 1811687282487328768 |
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| author | Iegre, Jessica Brear, Paul Baker, David J. Tan, Yaw Sing Atkinson, Eleanor L. Sore, Hannah F. O' Donovan, Daniel H. Hyvönen, Marko Spring, David R. Verma, Chandra Shekhar |
| author2 | School of Biological Sciences |
| author_facet | School of Biological Sciences Iegre, Jessica Brear, Paul Baker, David J. Tan, Yaw Sing Atkinson, Eleanor L. Sore, Hannah F. O' Donovan, Daniel H. Hyvönen, Marko Spring, David R. Verma, Chandra Shekhar |
| author_sort | Iegre, Jessica |
| collection | NTU |
| description | 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. |
| first_indexed | 2024-10-01T05:13:50Z |
| format | Journal Article |
| id | ntu-10356/106361 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T05:13:50Z |
| publishDate | 2019 |
| record_format | dspace |
| spelling | ntu-10356/1063612023-02-28T17:07:15Z Efficient development of stable and highly functionalised peptides targeting the CK2α/CK2β protein–protein interaction Iegre, Jessica Brear, Paul Baker, David J. Tan, Yaw Sing Atkinson, Eleanor L. Sore, Hannah F. O' Donovan, Daniel H. Hyvönen, Marko Spring, David R. Verma, Chandra Shekhar School of Biological Sciences Peptides Science::Biological sciences Protein–Protein Interaction 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. ASTAR (Agency for Sci., Tech. and Research, S’pore) Published version 2019-08-14T08:24:04Z 2019-12-06T22:09:52Z 2019-08-14T08:24:04Z 2019-12-06T22:09:52Z 2019 Journal Article Iegre, J., Brear, P., Baker, D. J., Tan, Y. S., Atkinson, E. L., Sore, H. F., . . . Spring, D. R. (2019). Efficient development of stable and highly functionalised peptides targeting the CK2α/CK2β protein–protein interaction. Chemical Science, 10(19), 5056-5063. doi:10.1039/C9SC00798A 2041-6520 https://hdl.handle.net/10356/106361 http://hdl.handle.net/10220/49635 10.1039/C9SC00798A en Chemical Science © 2019 The Author(s) (published by Royal Society of Chemistry). This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. 8 p. application/pdf |
| spellingShingle | Peptides Science::Biological sciences Protein–Protein Interaction Iegre, Jessica Brear, Paul Baker, David J. Tan, Yaw Sing Atkinson, Eleanor L. Sore, Hannah F. O' Donovan, Daniel H. Hyvönen, Marko Spring, David R. Verma, Chandra Shekhar 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 |
| title_full | Efficient development of stable and highly functionalised peptides targeting the CK2α/CK2β protein–protein interaction |
| title_fullStr | Efficient development of stable and highly functionalised peptides targeting the CK2α/CK2β protein–protein interaction |
| title_full_unstemmed | Efficient development of stable and highly functionalised peptides targeting the CK2α/CK2β protein–protein interaction |
| title_short | Efficient development of stable and highly functionalised peptides targeting the CK2α/CK2β protein–protein interaction |
| title_sort | efficient development of stable and highly functionalised peptides targeting the ck2α ck2β protein protein interaction |
| topic | Peptides Science::Biological sciences Protein–Protein Interaction |
| url | https://hdl.handle.net/10356/106361 http://hdl.handle.net/10220/49635 |
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