Chemical Probes to Study Copper Biology

Project Summary/Abstract
Copper is an essential metal nutrient that plays important roles in human health and disease. The potent redox
activity of copper is required for a diverse array of physiological processes including respiration, antioxidant
defense, and hormone and neurotransmitter biosynthesis and metabolism. However, dysregulated copper
homeostasis can contribute to cancer, metabolic diseases like obesity and diabetes, and heart and
neurodegenerative disorders, often through aberrant oxidative stress and damage pathways. We are
developing new chemical reagents that enable copper-specific imaging in biological models to help decipher
the contributions of copper to healthy and disease states, spanning the subcellular to cellular to animal level,
along with chemoproteomics approaches to identify and target copper-dependent disease vulnerabilities. The
scientific premise is that building a copper imaging and proteomics toolkit will provide foundational chemical
reagents to both further our understanding of the roles of copper in physiology and pathology and open new
avenues for therapeutic intervention. This competitive renewal application is driven by design innovations
where we invent new generalizable, activity-based sensing platforms for copper detection and activity-based
proteomics for copper-dependent disease targets, as well as scientific rigor in the synthesis and use of multiple
characterization techniques to apply these tools in cell and animal models. Specifically, we will pursue protein -
labeled copper probes to study how copper is stored, trafficked, and utilized at the subcellular and cellular
level, chemiluminescent indicators to enable dynamic and longitudinal copper imaging at the tissue and animal
level, and chemoproteomics approaches to identify copper-dependent druggable sites and covalent fragment
lead compounds against these targets.

Grant Number: 5R01GM079465-21
NIH Institute/Center: NIH
Principal Investigator: Christopher Chang