Design Principles for Intestinal Permeability of Cyclic Peptides

One of the most exciting facets of cyclic peptides is that they have the potential to be orally bioavailable, despite having physical properties well beyond the traditional “Rule-of-5” chemistry space (Lipinski et al., Adv Drug Deliv Rev. 23(1): 3–25, 1997). An important component of meeting this challenge is to design cyclic peptides with good intestinal permeability. Here we discuss the design principles for intestinal permeability that have been developed in recent year. These principles can be subdivided into three regimes: physical property guidelines, design strategies for the macrocyclic ring, and design strategies for side chains. The most important overall aims are to minimize solvent-exposed polarity while keeping size, flexibility, and lipophilicity within favorable ranges, thereby allowing peptide chemists to achieve intestinal permeability in addition to other important properties for their compounds, such as solubility and binding affinity. Here we describe a variety of design strategies that have been developed to help peptide chemists in this endeavor.