Achieving oral bioavailability of therapeutic macrocyclic peptides by bridging backbone chemistry with pharmacokinetics

Abstract

Full text embargo up to Dec 11, 2026 Macrocyclic peptides are emerging as very potential candidates for drug development. Due to the advancement in display technologies, macrocycles can target undruggable proteins. These molecules have the appropriate biochemical & therapeutic properties to provide advantages for both small molecules & antibodies. Still, most macrocycles cannot be given orally due to their low gastrointestinal absorption and rapid digestion. Our study shows that site-specific editing of the backbone of these macrocycles can enhance its drug-like properties. We focused on shielding the amide hydrogen bond acceptor (>C = O) & amide hydrogen bond donor (>N-H) to reduce the de-solvation penalty during membrane permeation. Additionally, altering the backbone amide of these macrocycles enhances their metabolic stability. In a proof of concept, we applied our strategy to four different macrocycles with very different physicochemical properties. With our strategy, we were able to develop several orally bioavailable macrocycles. In this process, we explored interesting parameters governing the permeability & compared the influence of hydrogen bond donor & acceptor to de-solvation. Finally, we applied these strategies to bioactive molecules to increase their drug-likeness without altering their bioactivity. Our strategy provides a unique therapeutic niche to macrocycles that can expand its pharmaceutical landscape.