Cyclic Penta- and Hexaleucine Peptides without N-Methylation Are Orally Absorbed.

Research paper by Timothy A TA Hill, Rink-Jan RJ Lohman, Huy N HN Hoang, Daniel S DS Nielsen, Conor C G CC Scully, W Mei WM Kok, Ligong L Liu, Andrew J AJ Lucke, Martin J MJ Stoermer, Christina I CI Schroeder, Stephanie S Chaousis, Barbara B Colless, Paul V PV Bernhardt, David J DJ Edmonds, David A DA Griffith, et al.

Indexed on: 15 Oct '14Published on: 15 Oct '14Published in: ACS Medicinal Chemistry Letters


Development of peptide-based drugs has been severely limited by lack of oral bioavailability with less than a handful of peptides being truly orally bioavailable, mainly cyclic peptides with N-methyl amino acids and few hydrogen bond donors. Here we report that cyclic penta- and hexa-leucine peptides, with no N-methylation and five or six amide NH protons, exhibit some degree of oral bioavailability (4-17%) approaching that of the heavily N-methylated drug cyclosporine (22%) under the same conditions. These simple cyclic peptides demonstrate that oral bioavailability is achievable for peptides that fall outside of rule-of-five guidelines without the need for N-methylation or modified amino acids.