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

The Keapl Nrf2 ARE pathway is an important antioxidant defense mechanism that protects cells from oxidative stress and the Keapl NrI2 protein protein interaction (PPE 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 'Keapl Nrf2 and they are electrophilic species that act by modifying the sulfhydryl groups of Keapl'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 Keapl NrI2 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 'Keapl Ketch domain protein. These non covalent direct inhibitors of Keapl Nrf2 PPI could potentially be developed into effective therapeutic or preventive agents for a variety of diseases and conditions. (C) 2015 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V. This is an open access article under thc CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).