Technische Universität München, Department Chemie, Institute for Advanced Study, Lichtenbergstrasse 4, 85748, Garching, Germany.
The Hebrew University of Jerusalem, Institutes of Chemistry and Drug Research, Israel.
Angew Chem Int Ed Engl. 2018 Oct 26;57(44):14414-14438. doi: 10.1002/anie.201807298. Epub 2018 Oct 3.
For decades, the development of peptides as potential drugs was aimed solely at peptides with the highest affinity, receptor selectivity, or stability against enzymatic degradation. However, optimization of their oral availability is highly desirable to establish orally active peptides as potential drug candidates for everyday use. A twofold optimization process is necessary to produce orally active peptides: 1) optimization of the affinity and selectivity and 2) optimization of the oral availability. These two steps must be performed sequentially for the rational design of orally active peptides. Nevertheless, additional knowledge is required to understand which structural changes increase oral availability, followed by incorporation of these elements into a peptide without changing its other biological properties. Considerable efforts have been made to understand the influence of these modifications on oral availability. One approach is to improve the oral availability of a peptide that has been previously optimized for biological activity, as described in (1) above. The second approach is to first identify an intestinally permeable, metabolically stable peptide scaffold and then introduce the functional groups necessary for the desired biological function. Previous approaches to achieving peptide oral availability have been claimed to have general applicability but, thus far, most of these solutions have not been successful in other cases. This Review discusses diverse chemical modifications, model peptides optimized for bioavailability, and orally active peptides to summarize the state of the research on the oral activity of peptides. We explain why no simple and straightforward strategy (i.e. a "magic bullet") exists for the design of an orally active peptide with a druglike biological function.
几十年来，人们一直致力于开发具有高亲和力、受体选择性或对酶降解稳定性的肽类药物。然而，提高其口服生物利用度对于将口服活性肽作为日常使用的潜在药物候选物非常重要。要开发口服活性肽，需要进行双重优化过程：1）优化亲和力和选择性，2）优化口服生物利用度。这两个步骤必须依次进行，才能合理设计口服活性肽。尽管如此，还需要额外的知识来了解哪些结构变化可以提高口服生物利用度，然后在不改变其其他生物学特性的情况下将这些元素整合到肽中。人们已经做出了相当大的努力来了解这些修饰对口服生物利用度的影响。一种方法是改进以前针对生物活性进行优化的肽的口服生物利用度，如上述（1）所述。第二种方法是首先确定一种肠内渗透性、代谢稳定的肽骨架，然后引入所需生物功能所需的功能基团。以前实现肽口服生物利用度的方法被认为具有普遍适用性，但到目前为止，这些解决方案在其他情况下大多没有成功。本文综述了不同的化学修饰、为提高生物利用度而优化的模型肽和口服活性肽，总结了肽口服活性研究的现状。我们解释了为什么对于设计具有类似药物生物功能的口服活性肽，没有一种简单直接的策略（即“万能钥匙”）。
