Abstract
Look at what the cat(ionic motif) dragged in! We report a general strategy to increase the cell permeability of beta(3)-peptides. Introduction of a minimal cationic motif within the folded structure of a high-affinity beta(3)-peptide ligand for hDM2 led to molecules with high 3(14)-helical structure, high hDM2 affinity and sufficient cell permeability to upregulate p53-dependent genes in live mammalian cells. Minimally cationic beta(3)-peptides represent the critical first step towards a class of protease-resistant peptidomimetics that might modulate intracellular biological pathways.