A cell-active cyclic peptide targeting the Nrf2/Keap1 protein–protein interaction

Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61989592%3A15310%2F23%3A73620903" target="_blank" >RIV/61989592:15310/23:73620903 - isvavai.cz</a>
Result on the web
<a href="https://pubs.rsc.org/en/content/articlepdf/2023/sc/d3sc04083f" target="_blank" >https://pubs.rsc.org/en/content/articlepdf/2023/sc/d3sc04083f</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1039/D3SC04083F" target="_blank" >10.1039/D3SC04083F</a>

Result language
angličtina
Original language name
A cell-active cyclic peptide targeting the Nrf2/Keap1 protein–protein interaction
Original language description
The disruption of the protein–protein interaction (PPI) between Nrf2 and Keap1 is an attractive strategy to counteract the oxidative stress that characterises a variety of severe diseases. Peptides represent a complementary approach to small molecules for the inhibition of this therapeutically important PPI. However, due to their polar nature and the negative net charge required for binding to Keap1, the peptides reported to date exhibit either mid-micromolar activity or are inactive in cells. Herein, we present a two-component peptide stapling strategy to rapidly access a variety of constrained and functionalised peptides that target the Nrf2/Keap1 PPI. The most promising peptide, P8-H containing a fatty acid tag, binds to Keap1 with nanomolar affinity and is effective at inducing transcription of ARE genes in a human lung epithelial cell line at sub-micromolar concentration. Furthermore, crystallography of the peptide in complex with Keap1 yielded a high resolution X-ray structure, adding to the toolbox of structures available to develop cell-permeable peptidomimetic inhibitors.
Czech name
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Czech description
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Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
10401 - Organic chemistry

Project
<a href="/en/project/GN22-07138O" target="_blank" >GN22-07138O: Conformationally-constrained peptide-drug conjugates as a platform for targeted therapeutics</a><br>
Continuities
P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Publication year
2023
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

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