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.