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

Publisher: Wiley-VCH Country of Publication: Germany NLM ID: 0370543 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1521-3773 (Electronic) Linking ISSN: 14337851 NLM ISO Abbreviation: Angew Chem Int Ed Engl Subsets: MEDLINE

Publication: <2004-> : Weinheim : Wiley-VCH
Original Publication: Weinheim/Bergstr. : New York, : Verlag Chemie ; Academic Press, c1962-

Copper*/chemistry ; Copper*/metabolism ; Nanofibers*/chemistry ; Homeostasis*/drug effects ; Peptides*/chemistry ; Peptides*/pharmacology ; Peptides*/metabolism ; Molecular Chaperones*/metabolism ; Molecular Chaperones*/chemistry; Humans ; Cell Line, Tumor ; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/chemistry

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.
(© 2024 The Author(s). Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

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R01 CA243033 United States CA NCI NIH HHS; Alexander von Humboldt-Stiftung; 860914 H2020 Marie Skłodowska-Curie Actions; R01CA24303 United States CA NCI NIH HHS

Keywords: Cancer therapeutics; Cu+ homeostasis interruption; Intracellular self-assembly; Oxidative stress

789U1901C5 (Copper)
0 (Peptides)
0 (Molecular Chaperones)
0 (Antineoplastic Agents)

Date Created: 20241024 Date Completed: 20241209 Latest Revision: 20241211

20241211

PMC11627128

10.1002/anie.202412477

39446574