Nuclear factor-erythroid 2 related factor 2 (Nrf2) is a redox-regulated transcription factor, able to induce production of a wide range of phase II and antioxidant enzymes. Increasingly, Nrf2 has been found to be a key mediator in the resolution of inflammation and the progression of chronic diseases. As a result, the induction of Nrf2-mediated genes is an attractive therapeutic target. Its negative regulator, Kelch-like ECH-associated protein 1 (Keap1) sequesters Nrf2 and targets it for ubiquitination. Upon detection of stress by key cysteine residues of Keap1, Nrf2 is released and translocates to the nucleus where it induces gene transcription. Known inducers of Nrf2 act by modification of Keap1 cysteine residues, altering the shape of the protein. The exact mechanism of this induction has not been determined and the off target interactions of these inducers are unknown. Therefore development of a non-covalent, highly specific inducer of Nrf2 is desirable, both for pathway elucidation and therapeutic use. One method to achieve this is to competitively block the Nrf2 binding site of Keap1. Previously, Lo et al. identified several peptides, based upon the Nrf2 protein, which show nanomolar binding to the Keap1 Kelch domain. Our current research has developed modified Nrf2 binding sequence peptides with cell penetrating sequences for the non-covalent induction of the Nrf2/Keap1 pathway. The ability of cell penetrating peptides (CPPs) to transport various cargos across cell membranes makes these Nrf2 binding sequence peptides bioavailable, and useful as both biological probes and therapeutic agents. Data from in vitro experiments in THP-1 monocytes suggest that the peptides enter cells rapidly, inducing downstream genes and reducing pro-inflammatory mediators in an established model of bacterial sepsis. Recent work has employed several routes that vary the CPPs utilised or remove the need for them, in order to increase both potency and stability.

Cell penetrating peptides targeting the Nrf2/Keap1 protein-protein interaction

246th National Meeting (2013)

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