Institute for Advanced Study and Center of Integrated Protein Science München (CIPSM), Department Chemie, Technische Universität München, Lichtenbergstraße 4, 85748 Garching (Deutschland), Germany.
Institute for Advanced Study and Center of Integrated Protein Science München (CIPSM), Department Chemie, Technische Universität München, Lichtenbergstraße 4, 85748 Garching (Deutschland), Germany.
Bioorg Med Chem. 2018 Jun 1;26(10):2766-2773. doi: 10.1016/j.bmc.2017.08.031. Epub 2017 Aug 31.
The renaissance of peptides in pharmaceutical industry results from their importance in many biological functions. However, low metabolic stability and the lack of oral availability of most peptides is a certain limitation. Whereas metabolic instability may be often overcome by development of small cyclic peptides containing d-amino acids, the very low oral availability of most peptides is a serious limitation for some medicinal applications. The situation is complicated because a twofold optimization - biological activity and oral availability - is required to overcome this problem. Moreover, most simple "rules" for achieving oral availability are not general and are applicable only to limited cases. Many structural modifications for increasing biological activities and metabolic stabilities of cyclic peptides have been described, of which N-alkylation is probably the most common. This mini-review focuses on the effects of N-methylation of cyclic peptides in strategies to optimize bioavailabilities.
医药行业中肽类物质的复兴源于其在多种生物学功能中的重要性。然而，大多数肽类物质代谢稳定性低且口服生物利用度差，这是一个明显的局限性。虽然通过开发含有 D-氨基酸的小环肽可以克服代谢不稳定性，但大多数肽类物质的口服生物利用度非常低，这对某些药物应用来说是一个严重的限制。情况变得复杂是因为需要进行双重优化——生物活性和口服生物利用度——才能克服这个问题。此外，大多数实现口服生物利用度的简单“规则”并不普遍，仅适用于有限的情况。已经描述了许多用于提高环状肽的生物活性和代谢稳定性的结构修饰方法，其中 N-烷基化可能是最常见的。这篇小型综述重点介绍了环状肽的 N-甲基化在优化生物利用度策略中的作用。
