Chronic, non-healing wounds of the skin are serious medical complications that affect over 6.5 million Americans, especially older adults. These wounds include pressure sores, diabetic foot ulcers and venous ulcers. There are numerous surgical and dressing treatments for these wounds, but because there are over 70,000 lower-limb amputations each year arising from these wounds, it is clear that new treatments are needed. Strikingly, there are almost no pharmaceutical therapies to accelerate healing of chronic wounds. A major contributor to chronic wounds is a prolonged inflammatory state, and reducing inflammation may be a way to accelerate healing of chronic wounds. Unfortunately, many commonly used anti-inflammatory drugs hinder chronic wound healing; thus, new ways of reducing inflammation are needed. An essential factor in wound healing and an important regulator of inflammation is Nrf2, a transcription factor that induces many cytoprotective and antioxidant genes. As seen in other inflammatory disorders, activating Nrf2 could be a useful therapeutic strategy to treat chronic skin wounds. Non-covalent Nrf2 activators can be developed by inhibiting the interaction of Nrf2 with its negative regulator, Keap1. We have developed non-covalent activators of Nrf2 as a means to promote wound healing in vitro and in vivo. These molecules inhibit the interaction of Keap1 and Nrf2 in vitro, and they induce the expression of Nrf2 target genes ex vivo. These molecules could form the basis of a pharmaceutical therapy to treat chronic skin wounds.

Optimization of non-covalent Nrf2 activators for use in models of chronic wound healing

255th National Meeting (2018)

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