Therapeutic stabilized alpha helices form a promising class of pharmaceuticals that have the potential to overcome the deficiencies of small molecule drugs in targeting protein-protein interactions. However, this field is being held back by several obstacles, including peptide stability, membrane permeability, and off-target toxicity, particularly in the case of peptides with intracellular targets such as MDM2. The p53/MDM2 interaction—a protein-protein interaction important in the formation and progression of many cancers, has been a highly sought-after target in the development of stabilized peptides. However, few peptides have been generated with serum-independent, on-target efficacy. This work describes a p53-like peptide that circumvents these obstacles using a dual-purpose stabilizing linker. By employing double-click stabilization with lipophilic linkers as well as peptide sequence optimization, we achieve enhanced cell membrane permeability and target binding with minimal off-target toxicity. We have found that lipophilicity improves maximum cellular uptake by up to 2 orders of magnitude and amino acid modification of key residues enhances both uptake and toxicity, with sub-micromolar IC50’s even in the presence of physiological concentrations of serum.

Design of double-click stabilized p53-like peptides with serum-independent on-target efficacy

253rd National Meeting (2017)

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