Exploring experimental and computational markers of cyclic peptides: Charting islands of permeability

Abstract

An increasing number of macrocyclic peptides that cross biological membranes are being reported, suggesting that it might be possible to develop peptides into orally bioavailable therapeutics; however, current understanding of what makes macrocyclic peptides cell permeable is still limited. Here, we synthesized 62 cyclic hexapeptides and characterized their permeability using in vitro assays commonly used to predict in vivo absorption rates, i.e. the Caco-2 and PAMPA assays. We correlated permeability with experimentally measured parameters of peptide conformation obtained using rapid methods based on chromatography and nuclear magnetic resonance spectroscopy. Based on these correlations, we..