? ? Research over the last decade has demonstrated that Keap1-Nrf2-antioxidant response element (ARE) system plays a key role in cancer chemoprevention by many chemicals like sulforaphane, curcumin, and epigallo- catechol gallate derived from natural sources such as fruits, vegetables, and tea products. Modification, by these natural electrophiles such as isothiocyanates and Michael acceptors, of sensitive cysteine residues found in the redox """"""""sensor"""""""" protein Keap1 is believed to be responsible for causing the dissociation of Keap1- Nrf2 complex and subsequent upregulation of oxidative stress response enzymes. To address concerns over the general use of purified natural thiol-reactive compounds as chemopreventive agents, novel short peptides and small organic molecules are designed and screened specifically for the inhibition of Keap1-Nrf2 interaction. These inhibitors will mimic the actions of reactive oxygen species and electrophiles like isothiocyanates and Michael acceptors in the induction of cytoprotective enzymes but will potentially be more selective and specific. Two structure-based approaches are proposed here to start from the recently available 3-D X-ray cocrystal structure of Keap1 Kelch domain with Nrf2 peptide to discover novel selective Keap1-Nrf2 inhibitors: a) to design conformationally restricted cyclic peptides to mimic the ?-hairpin loop of Nrf2 that interacts with Keap1 and b) to use in silico screening of virtual libraries for small molecules that could bind to Keap1 with high affinity and thus prevent the binding of Nrf2. These studies will provide important information about, and novel small molecule inhibitors of, the protein-protein interaction between Keap1 and Nrf2, and facilitate the development of more potent and selective Keap1-Nrf2 inhibitors as inducers of oxidative stress response enzymes. ? ? ?
