Improving the Cell Permeability of Polar Cyclic Peptides by Replacing Residues with Alkylated Amino Acids, Asparagines, and D-Amino Acids

The design, synthesis, and cell permeability of 19 hydrophilic macrocyclic peptides is presented. By systematically analyzing the impact of three different approaches (alkylated amino acids, asparagines, and D-amino acids) on the permeability of polar peptides, a well-defined strategy for optimizing cell permeability is provided. These three new methods can be used individually or in combination to effectively convert polar peptides into cell permeable molecules, and the results can be applied to the rapidly expanding peptide therapeutic industry.