Hill Timothy A, Lohman Rink-Jan, Hoang Huy N, Nielsen Daniel S, Scully Conor C G, Kok W Mei, Liu Ligong, Lucke Andrew J, Stoermer Martin J, Schroeder Christina I, Chaousis Stephanie, Colless Barbara, Bernhardt Paul V, Edmonds David J, Griffith David A, Rotter Charles J, Ruggeri Roger B, Price David A, Liras Spiros, Craik David J, Fairlie David P
Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, The University of Queensland , Brisbane, Queensland 4072, Australia.
School of Chemistry and Molecular Biosciences, The University of Queensland , Brisbane 4072, Australia.
ACS Med Chem Lett. 2014 Aug 4;5(10):1148-51. doi: 10.1021/ml5002823. eCollection 2014 Oct 9.
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.
基于肽的药物开发一直受到口服生物利用度低的严重限制，只有少数几种肽具有真正的口服生物利用度，主要是含有N-甲基氨基酸和少量氢键供体的环肽。在此，我们报告了没有N-甲基化且有五个或六个酰胺NH质子的环五亮氨酸和环六亮氨酸肽，在相同条件下表现出一定程度的口服生物利用度（4-17%），接近高度N-甲基化药物环孢素的口服生物利用度（22%）。这些简单的环肽表明，对于不符合五规则指导原则的肽，无需N-甲基化或修饰氨基酸即可实现口服生物利用度。
