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

ABSTRACT: 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.

SUBMITTER: Hill TA 

PROVIDER: S-EPMC4190638 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature