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 project 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: 3R01GM079465-21S1
NIH Institute/Center: NIH
Principal Investigator: Christopher Chang