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.