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 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–Nrf2PPI 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.

Insects: an underrepresented resource for the discovery of biologically active natural products

Nature has been the source of life-changing and-saving medications for centuries. Aspirin,penicillin and morphine are prime examples of Nature's gifts to medicine. These discoveries catalyzed the field of natural product drug discovery which has mostly focused on plants. However, insects have more than twice the number of species and entomotherapy has been in practice for as long as and often in conjunction with medicinal plants and is an important alternative to modern medicine in many parts of the world. Herein, an overview of current traditional medicinal applications of insects and characterization of isolated biologically active molecules starting from approximately 2010 is presented. Insect natural products reviewed were isolated from ants, bees, wasps, beetles, cockroaches, termites, flies, true bugs,moths and more. Biological activities of these natural products from insects include antimicrobial,antifungal, antiviral, anticancer, antioxidant, anti-inflammatory and immunomodulatory effects.

Cover story

The Keap1–Nrf2–ARE pathway is an important antioxidant defense mechanism that protects cells from oxidative stress.The homodimeric Keap1 protein functions as a redox sensor for environmental stress conditions and serves as a negative regulator of the transcription factor Nrf2 and ARE-controlled cytoprotective proteins.Under basal conditions,Nrf2 is bound