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.
CITATION STYLE
Hill, T. A., Lohman, R. J., Hoang, H. N., Nielsen, D. S., Scully, C. C. G., Kok, W. M., … Fairlie, D. P. (2014). Cyclic penta- and hexaleucine peptides without N -methylation are orally absorbed. ACS Medicinal Chemistry Letters, 5(10), 1148–1151. https://doi.org/10.1021/ml5002823
Mendeley helps you to discover research relevant for your work.