Deconstructing the Potency and Cell-Line Selectivity of Membranolytic Anticancer Peptides

Current cancer treatments damage healthy cells and tissues, causing short-term and long-term side effects. New treatments are desired that show greater selectivity toward cancer cells and evade the common mechanisms of multidrug resistance. Membranolytic anticancer peptides (mACPs) hold promise against cancer and multidrug resistance. Amphipathicity, hydrophobicity, and net charge of mACPs participate in their respective interactions with cell membranes and their overall inhibition of cancer cells. To support the design of cell-line selective mACPs, we investigated the relationships that amino acid composition, physicochemical properties, sequence motifs, and sequence homology could have with their potency and selectivity towards several healthy and cancer cell lines. Sequence length and net charge are known to affect the selectivity of mACPs between cancer and healthy cell lines. Our study reveals that increasing the net charge or flexibility (i. e., small and aliphatic residues) influences their selectivity between cancer cell lines with comparable lipid compositions.

Automated summary

Current cancer treatments have undesirable side effects on healthy cells and tissues, thus there is a need for new treatments that are more selective towards cancer cells and can overcome multidrug resistance. Membranolytic anticancer peptides (mACPs) show promise in this regard and their interactions with cell membranes, as well as their overall inhibition of cancer cells, are influenced by their amphipathicity, hydrophobicity, and net charge. In order to design mACPs that are selective towards specific cell lines, this study investigates the relationships between amino acid composition, physicochemical properties, sequence motifs, sequence homology, and their potency and selectivity towards healthy and cancer cell lines. It is found that sequence length and net charge play a role in the selectivity of mACPs between cancer and healthy cell lines, and increasing the net charge or flexibility of the peptides affects their selectivity among cancer cell lines with similar lipid compositions.