It is well established that one of the principal barriers to the passive permeation of peptides across membranes is the presence of multiple polar, highly hydrated, N-H amide bonds. Indeed, the unusually high bioavailability of certain peptide-based natural products, such as cyclosporine, can be ascribed to a high degree of N-methylation as well as the ability to adopt conformations that "hide" the remaining N-H units from solvent through intramolecular hydrogen bonding. 2 Thus, many strategies for improving the passive membrane permeability of MPs have focused on mimicking these characteristics. For example, some stapled peptides achieve this goal by stabilizing a helical structure with multiple intramolecular hydrogen bonds. Hydrophobic staples also generally improve permeability. An emerging strategy, nicely represented by a recent report from Suga and colleagues, 27 is to incorporate into the macrocycle non-amino acid units (in this case two pyridine rings) that are positioned to enter into intramolecular hydrogen bonds with N-H units in the peptide chain.