Breaking the rules with natural and non-natural cyclic peptides

The laboratory of Prof. Scott Lokey is studying the membrane permeability in molecules whose structures violate classical predictors of “drug-likeness” (e.g. Lipinski's "rule of five") based on molecular weight and polarity. Many of these ”rule breakers” are natural products such as the cyclic peptide cyclosporine A, a highly effective immunosuppressive drug that is orally bioavailable despite its molecular weight of ~1200. The Lokey lab is investigating the physico-chemical properties of molecules like cyclosporine and, using synthetic model systems, are uncovering interesting relationships between structure, conformation, and membrane permeability in these molecules.