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

被引：22

作者：

Steel, Richard J. ^{[1
]}

O'Connell, Maria A. ^{[1
]}

Searcey, Mark ^{[1
,2
]}

机构：

[1] Univ East Anglia, Sch Pharm, Norwich Res Pk, Norwich NR4 7TJ, Norfolk, England

[2] Univ East Anglia, Sch Chem, Norwich Res Pk, Norwich NR4 7TJ, Norfolk, England

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2018年 / 28卷 / 16期

关键词：

Nrf2; Keap1; Protein-protein interaction; Hexafluorobenzene; Peptide; PROTEIN-PROTEIN INTERACTION; KEAP1-NRF2; INTERACTION; NRF2; BINDING; DISCOVERY; GENE; INTERFACE; PROVIDES; PATHWAY; UPDATE;

D O I：

10.1016/j.bmcl.2018.03.003

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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 6-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 a glutamic acid to proline replacement leads to a new peptide with a K-i of 6.1 nM for the Nrf2/Keap1 binding interaction, although this does not translate into intracellular activity. (C) 2018 Elsevier Ltd. All rights reserved.

引用

页码：2728 / 2731

页数：4

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