4190057 - Activity-based sensing: Leveraging selective chemical reactivity to decipher biology at the atomic scale

Traditional strategies for developing selective imaging reagents rely on molecular recognition and static lock-and-key binding to achieve high specificity. We are advancing an alternative approach to chemical probe design, termed activity-based sensing, in which we exploit inherent differences in chemical reactivity as a foundation for distinguishing between chemical analytes that are similar in shape and size within complex biological systems. This presentation will focus on activity-based sensing approaches to visualize dynamic fluxes of metal ions, reactive oxygen species, and reactive carbon species and their signal/stress contributions to living systems, along with activity-based proteomics probes to identify their biological targets. As representative examples of new biological lessons learned from these chemical probes, we are advancing a new paradigm of transition metal signaling, where metal nutrients like copper and iron can serve as dynamic signals to regulate protein function by metalloallostery and influence basic behaviors such as eating and sleeping, as well as signal-atom signaling, where reversible redox interconversion between methionine and methionine sulfoxide reveals new ligandable hotspots for undruggable protein targets and pathways to accelerate the development of next-generation precision medicines that target redox disease vulnerabilities in cancer and neurodegeneration.