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

Area of Science:

• Biochemistry
• Nanotechnology
• Cancer Biology

Background:

• Copper (Cu+) is vital for cellular metabolism, and its dysregulation is linked to cancer progression.
• Targeting copper homeostasis in cancer is challenging due to low binding affinity of small molecule chelators.
• Intracellular copper chaperones possess high affinity and selectivity for Cu+.

Purpose of the Study:

• To develop a supramolecular strategy inspired by copper chaperones to disrupt copper homeostasis in cancer cells.
• To investigate the therapeutic potential of a self-assembling peptide targeting copper ions in cancer.

Main Methods:

• Design and synthesis of a peptide (Nap-FFMTCGGCR) with a Cu+-binding motif (MTCGGC).
• Investigation of peptide self-assembly into nanofibers within cancer cells.
• Assessment of peptide cytotoxicity, copper-dependent enzyme activity (SOD1), and oxidative stress induction in cancer cells.

Main Results:

• The peptide self-assembles into nanofibers with high affinity and selectivity for Cu+.
• Nap-FFMTCGGCR demonstrates significant cytotoxicity against triple-negative breast cancer cells (MDA-MB-231).
• The peptide impairs copper-dependent superoxide dismutase 1 (SOD1) activity and induces oxidative stress, with minimal effects on normal cells.

Conclusions:

• A supramolecular approach leveraging self-assembly and chaperone-inspired copper binding can effectively disrupt cancer cell copper homeostasis.
• This strategy offers a promising new avenue for developing targeted cancer therapeutics by exploiting metal ion dysregulation.