Charged cyclic hexapeptides: Updating molecular descriptors for permeability purposes.

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.

Lipophilicity of amyloid ß-peptide 12-28 and 25-35 to unravel their ability to promote hydrophobic and electrostatic interactions.

The growing interest for peptide therapeutics calls for new strategies to determine the physico-chemical properties responsible for the interactions of peptides with the environment. This study reports about the lipophilicity of two fragments of the amyloid ß-peptide, Aß 25-35 and Aß 12-28. Firstly, computational studies showed the limits of log D(7.4)oct in describing the lipophilicity of medium-sized peptides. Chromatographic lipophilicity indexes (expressed as log k', the logarithm of the retention factor) were then measured in three different systems to highlight the different skills of Aß 25-35 and Aß 12-28 in giving interactions with polar and apolar environments. CD studies were also performed to validate chromatographic experimental conditions. Results show that Aß 12-28 has a larger skill in promoting hydrophobic and electrostatic interactions than Aß 25-35. This finding proposes a strategy to determine the lipophilicity of peptides for drug discovery purposes but also gives insights in unraveling the debate about the aminoacidic region of Aß responsible for its neurotoxicity.