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

Abstract

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 Cu II ions across membranes. The peptide forms stable dimeric pores in the membrane and transports ions by a Cu 2 + /H + antiport mechanism. The ligand-induced excellent Cu II 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.

Small Peptidic Ionophore for Calcium Transport

“…with the central unit inducing selectivity. The observation reinforces our earlier findings with the alanine-based scaffolds that the functional groups at the C-terminus play a very important role in dictating ion-transport activity and selectivity. − The result is also in line with our recent report wherein Cu­(II) selectivity is induced by attaching a pybox ligand to the C-terminus of the tri-ala scaffold . The plots also indicated a Hill coefficient, that is, number of peptides associated with a single ion of ca.…”

“…15−17 The result is also in line with our recent report wherein Cu(II) selectivity is induced by attaching a pybox ligand to the C-terminus of the tri-ala scaffold. 26 The plots also indicated a Hill coefficient, that is, number of peptides associated with a single ion of ca. 1 for peptide 1.…”

“…Our group has recently reported the concept of utilizing ligands to induce cation selectivity. 26 Given the biological relevance of Ca 2+ ions, reported herein are peptide-derived transporters containing proximal pyridyl and triazole units for binding divalent ions (Figure 1). Pyridyl-triazole motifs have been exploited for binding divalent cations 27,28 and anions.…”

Mycobacterial Membranes as Actionable Targets for Lipid-Centric Therapy in Tuberculosis

“…More recently, the therapeutic effects of ionophores, including salinomycin, have gained increasing attention . With appropriate chemical modification to increase their selectivity toward Mtb membranes, ionophores can be used as anti- Mtb membrane-active agents . Boromycin is effective against mycobacteria but not against Gram-negative bacteria, suggesting that future studies are needed to elucidate its mechanism of action.…”

Progress and prospects toward supramolecular bioactive ion transporters

“…This includes a range of compounds like indole, benzimidazole/imidazole-based anionophores, [58][59][60][61] urea/thiourea-based anionophores, [62][63][64][65][66][67][68][69][70][71][72][73] squaramides 74,75 and other anion transporters. [76][77][78][79][80][81][82][83][84] Along with inducing apoptosis in cancer cells, interestingly, some of the synthetic anion transporters were also found to modulate autophagy in cancer cells, a combination that may prove to be highly effective in the fight against cancer. 74,80,85,86 However, a great challenge is there to achieve control over the action of the anionophores so as to keep the healthy cells safe.…”