Application of Post Solid-Phase Oxime Ligation to Fine-Tune Peptide–Protein Interactions
Protein–protein interactions (PPIs) represent an extremely attractive class of potential new targets for therapeutic intervention; however, the shallow extended character of many PPIs can render developing inhibitors against them as exceptionally difficult. Yet this problem can be made tractable by...
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| Format: | Article |
| Language: | English |
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MDPI AG
2020-06-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/25/12/2807 |
| _version_ | 1797564988982820864 |
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| author | Xue Zhi Zhao Fa Liu Terrence R. Burke |
| author_facet | Xue Zhi Zhao Fa Liu Terrence R. Burke |
| author_sort | Xue Zhi Zhao |
| collection | DOAJ |
| description | Protein–protein interactions (PPIs) represent an extremely attractive class of potential new targets for therapeutic intervention; however, the shallow extended character of many PPIs can render developing inhibitors against them as exceptionally difficult. Yet this problem can be made tractable by taking advantage of the fact that large interacting surfaces are often characterized by confined “hot spot” regions, where interactions contribute disproportionately to overall binding energies. Peptides afford valuable starting points for developing PPI inhibitors because of their high degrees of functional diversity and conformational adaptability. Unfortunately, contacts afforded by the 20 natural amino acids may be suboptimal and inefficient for accessing both canonical binding interactions and transient “cryptic” binding pockets. Oxime ligation represents a class of biocompatible “click” chemistry that allows the structural diversity of libraries of aldehydes to be rapidly evaluated within the context of a parent oxime-containing peptide platform. Importantly, oxime ligation represents a form of post solid-phase diversification, which provides a facile and empirical means of identifying unanticipated protein–peptide interactions that may substantially increase binding affinities and selectivity. The current review will focus on the authors’ use of peptide ligation to optimize PPI antagonists directed against several targets, including tumor susceptibility gene 101 (Tsg101), protein tyrosine phosphatases (PTPases) and the polo-like kinase 1 (Plk1). This should provide insights that can be broadly directed against an almost unlimited range of physiologically important PPIs. |
| first_indexed | 2024-03-10T19:04:41Z |
| format | Article |
| id | doaj.art-f1fe933219fa4f96a07449818e7308eb |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-10T19:04:41Z |
| publishDate | 2020-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-f1fe933219fa4f96a07449818e7308eb2023-11-20T04:12:40ZengMDPI AGMolecules1420-30492020-06-012512280710.3390/molecules25122807Application of Post Solid-Phase Oxime Ligation to Fine-Tune Peptide–Protein InteractionsXue Zhi Zhao0Fa Liu1Terrence R. Burke2Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USADiscovery Chemistry, Novo Nordisk Research Center Seattle, Seattle, WA 98109, USAChemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USAProtein–protein interactions (PPIs) represent an extremely attractive class of potential new targets for therapeutic intervention; however, the shallow extended character of many PPIs can render developing inhibitors against them as exceptionally difficult. Yet this problem can be made tractable by taking advantage of the fact that large interacting surfaces are often characterized by confined “hot spot” regions, where interactions contribute disproportionately to overall binding energies. Peptides afford valuable starting points for developing PPI inhibitors because of their high degrees of functional diversity and conformational adaptability. Unfortunately, contacts afforded by the 20 natural amino acids may be suboptimal and inefficient for accessing both canonical binding interactions and transient “cryptic” binding pockets. Oxime ligation represents a class of biocompatible “click” chemistry that allows the structural diversity of libraries of aldehydes to be rapidly evaluated within the context of a parent oxime-containing peptide platform. Importantly, oxime ligation represents a form of post solid-phase diversification, which provides a facile and empirical means of identifying unanticipated protein–peptide interactions that may substantially increase binding affinities and selectivity. The current review will focus on the authors’ use of peptide ligation to optimize PPI antagonists directed against several targets, including tumor susceptibility gene 101 (Tsg101), protein tyrosine phosphatases (PTPases) and the polo-like kinase 1 (Plk1). This should provide insights that can be broadly directed against an almost unlimited range of physiologically important PPIs.https://www.mdpi.com/1420-3049/25/12/2807peptidomimeticspeptide oxime ligationtethered fragment librariesprotein–protein interactions (PPIs)post solid-phase diversification |
| spellingShingle | Xue Zhi Zhao Fa Liu Terrence R. Burke Application of Post Solid-Phase Oxime Ligation to Fine-Tune Peptide–Protein Interactions Molecules peptidomimetics peptide oxime ligation tethered fragment libraries protein–protein interactions (PPIs) post solid-phase diversification |
| title | Application of Post Solid-Phase Oxime Ligation to Fine-Tune Peptide–Protein Interactions |
| title_full | Application of Post Solid-Phase Oxime Ligation to Fine-Tune Peptide–Protein Interactions |
| title_fullStr | Application of Post Solid-Phase Oxime Ligation to Fine-Tune Peptide–Protein Interactions |
| title_full_unstemmed | Application of Post Solid-Phase Oxime Ligation to Fine-Tune Peptide–Protein Interactions |
| title_short | Application of Post Solid-Phase Oxime Ligation to Fine-Tune Peptide–Protein Interactions |
| title_sort | application of post solid phase oxime ligation to fine tune peptide protein interactions |
| topic | peptidomimetics peptide oxime ligation tethered fragment libraries protein–protein interactions (PPIs) post solid-phase diversification |
| url | https://www.mdpi.com/1420-3049/25/12/2807 |
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