Title |
Cyclic Penta- and Hexaleucine Peptides without N‑Methylation Are Orally Absorbed
|
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Published in |
ACS Medicinal Chemistry Letters, August 2014
|
DOI | 10.1021/ml5002823 |
Pubmed ID | |
Authors |
Timothy A. Hill, Rink-Jan Lohman, Huy N. Hoang, Daniel S. Nielsen, Conor C. G. Scully, W. Mei Kok, Ligong Liu, Andrew J. Lucke, Martin J. Stoermer, Christina I. Schroeder, Stephanie Chaousis, Barbara Colless, Paul V. Bernhardt, David J. Edmonds, David A. Griffith, Charles J. Rotter, Roger B. Ruggeri, David A. Price, Spiros Liras, David J. Craik, David P. Fairlie |
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. |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
United Kingdom | 1 | 1% |
Unknown | 78 | 99% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Researcher | 26 | 33% |
Student > Ph. D. Student | 21 | 27% |
Student > Bachelor | 4 | 5% |
Student > Doctoral Student | 4 | 5% |
Professor > Associate Professor | 3 | 4% |
Other | 8 | 10% |
Unknown | 13 | 16% |
Readers by discipline | Count | As % |
---|---|---|
Chemistry | 46 | 58% |
Biochemistry, Genetics and Molecular Biology | 7 | 9% |
Pharmacology, Toxicology and Pharmaceutical Science | 6 | 8% |
Agricultural and Biological Sciences | 4 | 5% |
Engineering | 2 | 3% |
Other | 1 | 1% |
Unknown | 13 | 16% |