Cystine as an Ionophore: Redox‐Controlled Anion Transport and Toxicity Toward Triple Negative Breast Cancer Cells

Synthetic molecules that selectively transport anions across cellular membranes are an emerging class of therapeutics against cancer. Peptide-derived transporters are attractive for cancer therapy due to their biocompatibility. A disulfide tether is employed here to position two anion-binding hydrophobic tryptophan motifs in close proximity, thereby enhancing membrane insertion and anion selectivity. The tryptophan-flanked cystine functions as an anion carrier with a preference toward nitrate and chloride ions. Reduction of the disulfide to the corresponding free thiol substantially decreases anion transport activity. In situ reduction in vesicular systems, is governed by the membrane uptake of the disulfide. This loss in activity upon reduction to the corresponding cysteine establishes a unique class of anionophores that is active as the oxidized species rather than one activated by reduction. Extension to a cellular context showed a depletion in viability of triple negative MDA-MB-231 breast cancer cells by 50 µM of the transporter compared with untransformed MCF-10A breast cells. In co-cultures, the transporter shifted competitive viability in favor of the untransformed cells. These results establish cystine-based peptides as a chemically programmable class of anionophores that translate potentially into cancer-selective biological activity.