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

Kód výsledku v 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>

Výsledek na webu

<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>

Jazyk výsledku

angličtina

Název v původním jazyce

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

Popis výsledku v původním jazyce

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.

Název v anglickém jazyce

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

Popis výsledku anglicky

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.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10401 - Organic chemistry

Projekt

<a href="/cs/project/GN22-07138O" target="_blank" >GN22-07138O: Konformačně zamčené konjugáty peptidů a léčiv jako platforma pro cílená terapeutika</a><br>

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2023

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Chemical Science

ISSN

2041-6520

e-ISSN

2041-6539

Svazek periodika

14

Číslo periodika v rámci svazku

39

Stát vydavatele periodika

GB - Spojené království Velké Británie a Severního Irska

Počet stran výsledku

6

Strana od-do

10800-10805

Kód UT WoS článku

001072669500001

EID výsledku v databázi Scopus

2-s2.0-85173697602