Journal
ACS MEDICINAL CHEMISTRY LETTERS
Volume 5, Issue 10, Pages 1148-1151Publisher
AMER CHEMICAL SOC
DOI: 10.1021/ml5002823
Keywords
Oral bioavailability; absorption; peptides; rule of five; permeability
Categories
Funding
- Australian Research Council [FF0668733, DP1096290, LP110200213, CE140100011]
- Queensland Government (CIF)
- Australian National Health and Medical Research Council [1026501, 1027369]
- Australian Research Council [DP1096290, LP110200213] Funding Source: Australian Research Council
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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 hexaleucine 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.
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