A Chemical Technology for Target-Specific Redox Perturbation
Chemistry & Chemical Biology
In an emerging paradigm called “redox signaling”, exquisite cellular information transfer is choreographed by highly reactive chemical signals that are relayed through redox-linked modifications of specific sensor proteins. These chemical events in turn orchestrate specific decision-making responses in a cell. Disturbance to redox signaling pathways is tightly linked to many human disorders such as cancers, Alzheimer's and cardiovascular diseases. Conventional approaches in establishing links between disease and individual redox signaling events involve directly bathing the entire cell with the reactive chemicals and observing what happens. There are serious limitations to this approach because the entire cell is exposed to the reactive signal and timing and target-specificity are largely lost as the chemical signals hit many targets uncontrollably at different times. Thus responses that we read out are challenging to interpret because they are muddied by secondary effects and compensatory factors. The BYI award supports the research program in the Aye laboratory ultimately aimed at overcoming these technological limitations, and gaining precise control over precision targeting, in both space and time, of structurally diverse reactive chemical signals to specific proteins of interest in living cells and whole animals. We address this pressing need by developing a chemistry-driven approach to selectively flip a single redox switch in cells at a precise time. Our exciting early results suggest that this platform is able to pinpoint biological sufficiency with time-resolved information in activating pharmacologically important redox events. This technological development could prove a novel gateway to elucidate the basic biology of redox signaling deregulation that underlies many diseases.