Chaperone-Derived Copper(I)-Binding Peptide Nanofibers Disrupt Copper Homeostasis in Cancer Cells

Copper (Cu) is a transition metal that plays crucial roles in cellular metabolism. Cu homeostasis is upregulated in many cancers and contributes to tumorigenesis. However, therapeutic strategies to target Cu homeostasis in cancer cells are rarely explored because small molecule Cu chelators have poor binding affinity in comparison to the intracellular Cu chaperones, enzymes, or ligands. To address this challenge, we introduce a Cu chaperone-inspired supramolecular approach to disrupt Cu homeostasis in cancer cells that induces programmed cell death. The Nap-FFMTCGGCR peptide self-assembles into nanofibers inside cancer cells with high binding affinity and selectivity for Cu due to the presence of the unique MTCGGC motif, which is conserved in intracellular Cu chaperones. Nap-FFMTCGGCR exhibits cytotoxicity towards triple negative breast cancer cells (MDA-MB-231), impairs the activity of Cu dependent co-chaperone super oxide dismutase1 (SOD1), and induces oxidative stress. In contrast, Nap-FFMTCGGCR has minimal impact on normal HEK 293T cells. Control peptides show that the self-assembly and Cu binding must work in synergy to successfully disrupt Cu homeostasis. We show that assembly-enhanced affinity for metal ions opens new therapeutic strategies to address disease-relevant metal ion homeostasis.