Cyclic Penta- and Hexaleucine Peptides without N-Methylation Are Orally Absorbed
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- 作者：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
- 刊名：ACS Medicinal Chemistry Letters
- 出版年：2014
- 出版时间：October 9, 2014
- 年：2014
- 卷：5
- 期：10
- 页码：1148-1151
- 全文大小：250K
- ISSN：1948-5875
文摘
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鈥?7%) 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.