End-to-End Backbone Cyclization Enhances Passive Permeability of bRo5 Oligomeric Depsipeptides with Nonlinear Size Dependence.

A majority of drugs are small molecules that satisfy Lipinski's Rule-of-Five (Ro5), but efforts to target topologically complex biomolecular interactions have reignited interest in nonconforming molecular therapeutics, dubbed "beyond Ro5 (bRo5)". Broadly useful design principles for bRo5 molecules are few in number, although several studies have highlighted the benefit to bioavailability and proteolytic stability that can result from the introduction of a constraining ring into conformationally mobile peptides. Here we show that a linear oligomeric depsipeptide (OD) template can be leveraged to link size to permeability, while the corresponding cyclic oligomeric depsipeptide (COD) series is used to determine the impact of cyclization as an added conformational constraint. Unexpectedly, certain macrocycle sizes confer a greater benefit to permeability than others.