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The chameleonic behavior has been emerged as a key conformational property to achieve high membrane permeability and oral bioavailability for macrocyclic peptides in the beyond rule of five (bRo5) chemical space. Some natural or synthetic products (e.g., cyclosporin A (CsA)) were investigated to understand the chameleonic behavior and identify the structural features, but general guidelines to design chameleonic molecules are still unknown. In this study, the chameleonic behavior of cyclosporin O (CsO) and its derivatives modifying the side chains was evaluated by NMR spectroscopy, and its effect on membrane permeability, cyclophilin A (CypA) binding, and the pharmacokinetic profile was described. CsO showed weaker chameleonic behavior than CsA even though a similar closed conformation was observed for CsA and CsO. The weaker chameleonic behavior of CsO explained the decrease in membrane permeability and CypA binding. It led to a higher plasma concentration and moderate oral bioavailability (F = 12%). We believe that CsO scaffold can afford insight into understanding the chameleonic behavior and designing membrane permeable and orally bioavailable drugs in the bRo5 chemical space.
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KCS