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.

BioScience Research and Early Development Respiratory and Immunology BioPharmaceuticals R and D AstraZeneca Pepparedsleden 1 43183 Gothenburg Sweden

Department of Organic Chemistry Palacky University Olomouc Tr 17 Listopadu 12 77900 Olomouc Czech Republic

Mechanistic and Structural Biology Discovery Sciences BioPharmaceuticals R and D AstraZeneca Pepparedsleden 1 43183 Gothenburg Sweden

Medicinal Chemistry Research and Early Development Respiratory and Immunology BioPharmaceuticals R and D AstraZeneca Pepparedsleden 1 43183 Gothenburg Sweden

Yusuf Hamied Department of Chemistry Lensfield Road CB2 1EW Cambridge UK

Citace poskytuje Crossref.org