Discovery of direct inhibitors of Keap1–Nrf2 protein–protein interaction as potential therapeutic and preventive agents

The Keap1–Nrf2–ARE pathway is an important antioxidant defense mechanism that protects cells from oxidative stress and the Keap1–Nrf2 protein–protein interaction (PPI) has become an important drug target to upregulate the expression of ARE-controlled cytoprotective oxidative stress response enzymes...

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Main Authors:	Dhulfiqar Ali Abed, Melanie Goldstein, Haifa Albanyan, Huijuan Jin, Longqin Hu
Format:	Article
Language:	English
Published:	Elsevier 2015-07-01
Series:	Acta Pharmaceutica Sinica B
Subjects:	Oxidative stress Keap1 Nrf2 Direct inhibitors of protein–protein interaction High throughput screening assays Structure–activity relationships X-ray crystallography
Online Access:	http://www.sciencedirect.com/science/article/pii/S2211383515000829

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spelling	doaj-ebf86f3596dc42509b53832e5a147ea02020-11-24T22:50:35ZengElsevierActa Pharmaceutica Sinica B2211-38352211-38432015-07-015428529910.1016/j.apsb.2015.05.008Discovery of direct inhibitors of Keap1–Nrf2 protein–protein interaction as potential therapeutic and preventive agentsDhulfiqar Ali Abed0Melanie Goldstein1Haifa Albanyan2Huijuan Jin3Longqin Hu4Department of Medicinal Chemistry, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway 08854, USADepartment of Medicinal Chemistry, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway 08854, USADepartment of Medicinal Chemistry, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway 08854, USADepartment of Medicinal Chemistry, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway 08854, USADepartment of Medicinal Chemistry, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway 08854, USAThe Keap1–Nrf2–ARE pathway is an important antioxidant defense mechanism that protects cells from oxidative stress and the Keap1–Nrf2 protein–protein interaction (PPI) has become an important drug target to upregulate the expression of ARE-controlled cytoprotective oxidative stress response enzymes in the development of therapeutic and preventive agents for a number of diseases and conditions. However, most known Nrf2 activators/ARE inducers are indirect inhibitors of Keap1–Nrf2 PPI and they are electrophilic species that act by modifying the sulfhydryl groups of Keap1׳s cysteine residues. The electrophilicity of these indirect inhibitors may cause "off-target" side effects by reacting with cysteine residues of other important cellular proteins. Efforts have recently been focused on the development of direct inhibitors of Keap1–Nrf2 PPI. This article reviews these recent research efforts including the development of high throughput screening assays, the discovery of peptide and small molecule direct inhibitors, and the biophysical characterization of the binding of these inhibitors to the target Keap1 Kelch domain protein. These non-covalent direct inhibitors of Keap1–Nrf2 PPI could potentially be developed into effective therapeutic or preventive agents for a variety of diseases and conditions.http://www.sciencedirect.com/science/article/pii/S2211383515000829Oxidative stressKeap1Nrf2Direct inhibitors of protein–protein interactionHigh throughput screening assaysStructure–activity relationshipsX-ray crystallography
collection	DOAJ
language	English
format	Article
sources	DOAJ
author	Dhulfiqar Ali Abed Melanie Goldstein Haifa Albanyan Huijuan Jin Longqin Hu
spellingShingle	Dhulfiqar Ali Abed Melanie Goldstein Haifa Albanyan Huijuan Jin Longqin Hu Discovery of direct inhibitors of Keap1–Nrf2 protein–protein interaction as potential therapeutic and preventive agents Acta Pharmaceutica Sinica B Oxidative stress Keap1 Nrf2 Direct inhibitors of protein–protein interaction High throughput screening assays Structure–activity relationships X-ray crystallography
author_facet	Dhulfiqar Ali Abed Melanie Goldstein Haifa Albanyan Huijuan Jin Longqin Hu
author_sort	Dhulfiqar Ali Abed
title	Discovery of direct inhibitors of Keap1–Nrf2 protein–protein interaction as potential therapeutic and preventive agents
title_short	Discovery of direct inhibitors of Keap1–Nrf2 protein–protein interaction as potential therapeutic and preventive agents
title_full	Discovery of direct inhibitors of Keap1–Nrf2 protein–protein interaction as potential therapeutic and preventive agents
title_fullStr	Discovery of direct inhibitors of Keap1–Nrf2 protein–protein interaction as potential therapeutic and preventive agents
title_full_unstemmed	Discovery of direct inhibitors of Keap1–Nrf2 protein–protein interaction as potential therapeutic and preventive agents
title_sort	discovery of direct inhibitors of keap1–nrf2 protein–protein interaction as potential therapeutic and preventive agents
publisher	Elsevier
series	Acta Pharmaceutica Sinica B
issn	2211-3835 2211-3843
publishDate	2015-07-01
description	The Keap1–Nrf2–ARE pathway is an important antioxidant defense mechanism that protects cells from oxidative stress and the Keap1–Nrf2 protein–protein interaction (PPI) has become an important drug target to upregulate the expression of ARE-controlled cytoprotective oxidative stress response enzymes in the development of therapeutic and preventive agents for a number of diseases and conditions. However, most known Nrf2 activators/ARE inducers are indirect inhibitors of Keap1–Nrf2 PPI and they are electrophilic species that act by modifying the sulfhydryl groups of Keap1׳s cysteine residues. The electrophilicity of these indirect inhibitors may cause "off-target" side effects by reacting with cysteine residues of other important cellular proteins. Efforts have recently been focused on the development of direct inhibitors of Keap1–Nrf2 PPI. This article reviews these recent research efforts including the development of high throughput screening assays, the discovery of peptide and small molecule direct inhibitors, and the biophysical characterization of the binding of these inhibitors to the target Keap1 Kelch domain protein. These non-covalent direct inhibitors of Keap1–Nrf2 PPI could potentially be developed into effective therapeutic or preventive agents for a variety of diseases and conditions.
topic	Oxidative stress Keap1 Nrf2 Direct inhibitors of protein–protein interaction High throughput screening assays Structure–activity relationships X-ray crystallography
url	http://www.sciencedirect.com/science/article/pii/S2211383515000829
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Discovery of direct inhibitors of Keap1–Nrf2 protein–protein interaction as potential therapeutic and preventive agents

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