Scientists at Scripps Research have uncovered a connection between a cell's sugar metabolism and its antioxidant response. Targeting this link, the researchers identified a small molecule capable of activating the antioxidant response, a potential therapy for a range of diseases involving oxidative stress such as chronic kidney disease, neurodegeneration, and autoimmune disease. They reported their discovery recently in Nature.
"This study demonstrates that there's clear cross-talk between central carbon metabolism and the antioxidant response and opens the door to develop these findings to target a range of diseases," says Luke Lairson, Ph.D., co-senior author of the study. "The small molecule we developed targets the glycolysis pathway in a reversible way to activate the antioxidant response, which could represent a new strategy for developing drugs to turn on this protective pathway."
The key player in this cross-talk is a protein called KEAP1, which acts as a sensor for potentially damaging reactive molecules in cells. When these reactive molecules build up, KEAP1 triggers the antioxidant stress response to clean them up. Because reactive molecules are linked to the development of so many diseases—from cancers to autoimmune and neurological disorders—scientists are searching for a way to target KEAP1 and take control of the cell stress response. There has been good progress in finding a "covalent" mechanism to directly target KEAP1, but this approach has the downside of potentially affecting other proteins and causing side effects.
To discover alternative mechanisms to activate this pathway, the Scripps Research scientists decided to employ a chemical genetics-based approach to find non-covalent activators of KEAP1. "We identified a completely new mechanism by first searching for molecules that activate this pathway in an unbiased cell-based screen—and then retroactively looking for their targets and mechanisms of action," says Michael Bollong, Ph.D., first author of the new study. This approach led the scientists to a molecule called CBR-470-1, which was then optimized by researchers at Calibr, a nonprofit drug discovery division of Scripps Research.