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

Richard J. Steel; Maria A. O'Connell; Mark Searcey

doi:10.1016/j.bmcl.2018.03.003

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

Richard J. Steel, Maria A. O'Connell, Mark Searcey

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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.

Original language	English
Pages (from-to)	2728-2731
Number of pages	4
Journal	Bioorganic & Medicinal Chemistry Letters
Volume	28
Issue number	16
Early online date	3 Mar 2018
DOIs	https://doi.org/10.1016/j.bmcl.2018.03.003
Publication status	Published - 1 Sep 2018

Keywords

NRF2 or nuclear factor erythroid 2 [NF-E2]-related factor 2
Keap1
protein-protein interaction
hexafluorobenzene
peptide

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10.1016/j.bmcl.2018.03.003

Accepted manuscriptAccepted author manuscript, 649 KBLicence: CC BY-NC-ND

Maria O'Connell
- M.OConnelluea.acuk
- Faculty of Science - Associate Dean for Research
- School of Chemistry, Pharmacy and Pharmacology - Professor of Cell Biology
- Molecular and Tissue Pharmacology - Group Lead
- HealthUEA - Steering Committee Member
Person: Research Group Member, Academic, Teaching & Research
Mark Searcey
- M.Searceyuea.acuk
- School of Chemistry, Pharmacy and Pharmacology - Pro-Vice-Chancellor
- Norwich Institute for Healthy Aging - Member
Person: Research Centre Member, Academic, Teaching & Research

Cite this

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title = "Perfluoroarene-based peptide macrocycles that inhibit the Nrf2/Keap1 interaction",

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. ",

keywords = "NRF2 or nuclear factor erythroid 2 [NF-E2]-related factor 2, Keap1, protein-protein interaction, hexafluorobenzene, peptide",

author = "Steel, {Richard J.} and O'Connell, {Maria A.} and Mark Searcey",

year = "2018",

month = sep,

day = "1",

doi = "10.1016/j.bmcl.2018.03.003",

language = "English",

volume = "28",

pages = "2728--2731",

journal = "Bioorganic & Medicinal Chemistry Letters",

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publisher = "Elsevier",

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T1 - Perfluoroarene-based peptide macrocycles that inhibit the Nrf2/Keap1 interaction

AU - Steel, Richard J.

AU - O'Connell, Maria A.

AU - Searcey, Mark

PY - 2018/9/1

Y1 - 2018/9/1

N2 - 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.

AB - 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.

KW - NRF2 or nuclear factor erythroid 2 [NF-E2]-related factor 2

KW - Keap1

KW - protein-protein interaction

KW - hexafluorobenzene

KW - peptide

U2 - 10.1016/j.bmcl.2018.03.003

DO - 10.1016/j.bmcl.2018.03.003

M3 - Article

VL - 28

SP - 2728

EP - 2731

JO - Bioorganic & Medicinal Chemistry Letters

JF - Bioorganic & Medicinal Chemistry Letters

SN - 0960-894X

IS - 16

ER -

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

Abstract

Keywords

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Profiles

Maria O'Connell

Mark Searcey

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