Perfluoroarene-based peptide macrocycles that inhibit the Nrf2/Keap1 interaction

Steel, Richard J., O'Connell, Maria A. ORCID: https://orcid.org/0000-0002-0267-0951 and Searcey, Mark ORCID: https://orcid.org/0000-0003-2273-8949 (2018) Perfluoroarene-based peptide macrocycles that inhibit the Nrf2/Keap1 interaction. Bioorganic & Medicinal Chemistry Letters, 28 (16). pp. 2728-2731. ISSN 0960-894X

Preview

PDF (Accepted manuscript) - Accepted Version Available under License Creative Commons Attribution Non-commercial No Derivatives. Download (664kB) | Preview

Abstract

The Nrf2/Keap1 interaction is a target in the development of new therapeutic agents, where inhibition of the interaction activates Nrf2 and leads to the generation of downstream anti-inflammatory effects. Peptides that mimic the β-turn in the Keap1 active site and are constrained by a disulfide bridge have high affinity for Keap1 but no intracellular activity. The introduction of a perfluoroalkyl- bridging group to constrain the peptides, coupled with glutamic acid to proline replacement leads to a new peptide with a Ki of 6.1 nM for the Nrf2/Keap1 binding interaction, although this does not translate into intracellular activity.

Item Type:	Article
Uncontrolled Keywords:	nrf2 or nuclear factor erythroid 2 [nf-e2]-related factor 2,keap1,protein-protein interaction,hexafluorobenzene,peptide
Faculty \ School:	Faculty of Science > School of Pharmacy (former - to 2024) Faculty of Science > School of Chemistry (former - to 2024)
UEA Research Groups:	Faculty of Science > Research Groups > Chemical Biology and Medicinal Chemistry (former - to 2021) Faculty of Science > Research Groups > Molecular and Tissue Pharmacology
Depositing User:	Pure Connector
Date Deposited:	02 Mar 2018 11:30
Last Modified:	04 Dec 2024 01:28
URI:	https://ueaeprints.uea.ac.uk/id/eprint/66414
DOI:	10.1016/j.bmcl.2018.03.003

Downloads

Actions (login required)

View Item