AI Designs Permeable Macrocycles for Improved Oral Drug Delivery

Macrocycles, a class of cyclic peptides and natural products, are increasingly recognized for their therapeutic potential due to their high target specificity and potency. However, their large molecular size often leads to poor cell permeability and oral bioavailability, significantly hindering their development into effective oral drugs, especially for intracellular targets. Existing computational and experimental design strategies frequently struggle to simultaneously optimize both target binding affinity and membrane permeability, creating a critical bottleneck in drug discovery.

The DPO-designed macrocycles exhibited significantly enhanced permeability profiles while largely retaining target binding affinity. The lead compound, DPO-Macro-1, demonstrated a remarkable 3.5-fold increase in apparent permeability coefficient (Papp) in Caco-2 cells compared to Cyclosporin A (p<0.001), indicating superior intestinal absorption potential. In the in vivo rat study, DPO-Macro-1 achieved an oral bioavailability of 43%, representing a 2.8-fold improvement over Cyclosporin A's 15% (p<0.01). Importantly, DPO-Macro-1 maintained potent binding to its primary target, cyclophilin A, with an IC50 of 12 nM, which is highly comparable to Cyclosporin A's 10 nM. DPO-Macro-1 achieved a 2.8-fold increase in oral bioavailability in rats while maintaining potent target binding, demonstrating the DPO framework's success in simultaneously optimizing critical drug properties.