Ligand Induced CuII Transport Restricts Cancer and Mycobacterial Growth: Towards a Plug‐and‐Select Ion Channel Scaffold

• Published in: Chembiochem : a European journal of chemical biology 2021-04, Vol.22 (8), p.1424-1429
• Main Authors: Saha, Parichita, Kumari Agarwala, Prema, Dadhich, Ruchika, Adhyapak, Pranav, Kapoor, Shobhna, Madhavan, Nandita
• Format: Article
• Language: English
• Subjects: Antiinfectives and antibacterials; Antiport; C-Terminus; Cancer; Cell death; Channel pores; Copper; copper transport; Homeostasis; Ion channels; ion selectivity; Ions; Ligands; Membrane permeability; Membranes; Peptides; Scaffolds; Selectivity; Therapeutic targets
• ISSN: 1439-4227; 1439-7633
• DOI: 10.1002/cbic.202000731

Synthetic channels with high ion selectivity are attractive drug targets for diseases involving ion dysregulation. Achieving selective transport of divalent ions is highly challenging due their high hydration energies. A small tripeptide amphiphilic scaffold installed with a pybox ligand selectively transports CuII ions across membranes. The peptide forms stable dimeric pores in the membrane and transports ions by a Cu2+/H+ antiport mechanism. The ligand‐induced excellent CuII selectivity as well as high membrane permeability of the peptide is exploited to promote cancer cell death. The peptide's ability to restrict mycobacterial growth serves as seeds to evolve antibacterial strategies centred on selectively modulating ion homeostasis in pathogens. This simple peptide can potentially function as a universal, yet versatile, scaffold wherein the ion selectivity can be precisely controlled by modifying the ligand at the C terminus. A hole in more than one: A peptide scaffold with a pybox ligand selectively transports CuII across simple and complex lipid membranes. The peptide forms stables pores in the membranes and transports ions by an antiport mechanism. Such peptides could facilitate Cu transport across mycobacterial or cancer cell membranes as an effective anti‐infective strategy or to induce cell death.