Abstract
Selectively targeting the membrane-perturbing potential of peptides towards a distinct cellular phenotype allows one to target distinct populations of cells. We report the de novo design of a new class of peptide whose ability to perturb cellular membranes is coupled to an enzyme-mediated shift in the folding potential of the peptide into its bioactive conformation. Cells rich in negatively charged surface components that also highly express alkaline phosphatase, for example many cancers, are susceptible to the action of the peptide. The unfolded, inactive peptide is dephosphorylated, shifting its conformational bias towards cell-surface-induced folding to form a facially amphiphilic membrane-active conformer. The fate of the peptide can be further tuned by peptide concentration to affect either lytic or cell-penetrating properties, which are useful for selective drug delivery. This is a new design strategy to afford peptides that are selective in their membrane-perturbing activity.