Charged cyclic hexapeptides: Updating molecular descriptors for permeability purposes

• Published in: European journal of pharmaceutical sciences Vol. 122; pp. 85 - 93
• Main Authors: Ermondi, G., Vallaro, M., Camacho-Leal, M.P., Potter, T., Visentin, S., Caron, G.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 15.09.2018
• Subjects: Chromatographic indexes; Cyclic hexapeptides; HILIC; IAM; Intramolecular hydrogen bonding; Ionization; Lipophilicity; MD simulations; Intramolecular hydrogen bonding; Chromatographic indexes; IAM; Ionization; MD simulations; Cyclic hexapeptides; HILIC; Lipophilicity
• ISSN: 0928-0987; 1879-0720
• DOI: 10.1016/j.ejps.2018.06.021

Three polar cyclic hexapeptides differently charged at physiological pH (1 = neutral, 2 = anionic, 3 = cationic) were synthesized and their cell permeability measured. Lipophilicity in octanol/water didn't account for the higher permeability of the cationic derivative but three chromatographic indexes (log KwIAM, log k′ HILIC and log k′ c-HILIC) were more efficient to this respect. NMR amide chemical shift temperature coefficients (ΔδNH/ΔT) were used to explore the IMHB network of the backbone. MD simulations in different environments (water, chloroform and DMPC lipid bilayer) highlighted that the charged amino group of the lysine moiety of 3 is not involved in the formation of any IMHB in water whereas a different behavior is registered in chloroform and DMPC lipid bilayer. Overall this paper highlights how a combination of experimental and computational approaches could help in comparing permeability and physicochemical properties of neutral and charged cyclic peptides. [Display omitted]