Funder – NIH

Title – Non-Covalent Nrf2 Activators for the Treatment of Chronic Wounds

Description

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. There are a number of covalent Nrf2 activators, but they are not selective for Nrf2, which is problematic because some of the off-target effects of these molecules are at proteins that hinder chronic wound healing. Thus, pharmacologic activation of Nrf2 with non-covalent small molecules will accelerate wound healing, which could lead to new therapeutics to treat chronic wounds. Our lab, in collaboration with Drs. DiPietro and Reddy labs at UIC, are using metabolism and pharmacokinetics studies, to develop high-affinity, metabolically stable, in vivo probes of Nrf2 activation for chronic wounds. These experiments are significant because they will develop novel in vivo probes of non-covalent Nrf2 activation, and they are innovative because they will open up new therapeutic strategies to treat chronic wounds.