Design and Discovery of Orally Bioavailable Macrocycles: Toward Orally Bioavailable Peptide Therapeutics

Achieving cell permeability and oral bioavailability are key challenges for peptide therapeutics. In this chapter, we review the evolution of and recent advances in rational approaches for the design of cell-permeable, orally bioavailable macrocycles, showing representative examples and highlighting common design principles. Following these design principles while achieving a desired bioactivity in a given compound constitutes an additional challenge. In this context, creating a synergy between passive cell-permeability/oral bioavailability of peptide macrocycles in the context of large-scale peptide arrays would enable the discovery of therapeutics for challenging targets. Herein, we discuss these challenges and multiple distinct approaches toward achieving such a synergy.