Improving oral bioavailability of peptides by multiple N-methylation: Somatostatin analogues
Improving oral bioavailability of peptides by multiple N-methylation: Somatostatin analogues
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DOI：
10.1002/anie.200705797
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发表时间：
2008-01-01
影响因子：
16.6
通讯作者：
Kessler, Horst
中科院分区：
文献类型：
--
作者：
Biron, Eric;Chatterjee, Jayanta;Kessler, Horst
口服给药后肽的低生物利用度归因于它们在胃肠道中的失活，这是通过肠细胞刷状缘处表达的各种肽酶在肠壁中增强酶降解来实现的[1]，以及肠道渗透性差。[2]此外，在全身血液循环中肽对肽酶的不稳定性导致快速消除（即半衰期短）。这些因素限制了肽在临床环境中作为治疗剂的用途。已经使用了几种策略来减少酶裂解和吸收到全身血液循环中，包括前药方法，肽模拟物和结构修饰，例如聚乙二醇（PEG）的共价连接，[3]脂化，[4]和化学修饰，例如环化，[5] d-氨基酸取代和N-甲基化。[6]环肽显示出改善的化学稳定性，从而与其线性对应物相比显示出更长的生物半衰期。[7]然而，需要额外的修饰以产生具有增强的酶稳定性和改善的口服生物利用度的肽。建议用于改善肽的酶稳定性的技术之一是N-甲基化。[8，9]我们最近开发了一种简化的方法，该方法允许在固体支持物上快速有效地对肽进行多重N-甲基化。[10]这种简化的合成能力使我们研究了肽骨架的多重N-甲基化对其构象和生物活性的影响。[11受高度N-甲基化的移植药物环孢菌素A的生物利用度的启发，尽管它违反了Lipinski关于口服生物利用度的所有规则，但它可以口服给药;[13]我们假设这种生物利用度是其多重N-甲基化和环化的结果。因此，可以通过环肽的多重N-甲基化来克服提供生物活性和受体选择性的肽的上述生物利用度缺点。因此，我们计划筛选Veber-Hirschmann环状六肽环（-PFwKTF-）（1;图1）的所有可能的N-甲基化类似物的完整文库，据报道其对sst 2和
Low bioavailability of peptides following oral administration is attributed to their inactivation in the gastro–intestinal tract through enhanced enzymatic degradation in the gut wall by a variety of peptidases expressed at the enterocytes brush border,[1] and to poor intestinal permeation.[2] In addition, the instability of peptides toward peptidases in the systemic blood circulation causes rapid elimination (ie, short half-life). These factors limit the use of peptides as therapeutic agents in the clinical setting. Several strategies have been used to reduce enzymatic cleavage and uptake into the systemic blood circulation, including prodrug approaches, peptidomimetics, and structural modifications, such as covalent attachment of polyethylene glycol (PEG),[3] lipidation,[4] and chemical modifications, for example, cyclization,[5] d-amino acid substitution, and N-methylation.[6] Cyclic peptides show improved chemical stability and thereby display longer biological half-life compared to their linear counterparts.[7] Yet, additional modifications are required to generate peptides with enhanced enzymatic stability and improved oral bioavailability. One of the techniques suggested to improve the enzymatic stability of peptides is N-methylation.[8, 9] We recently developed a simplified method which allows fast and efficient multiple N-methylation of peptides on solid support.[10] This simplified synthetic capability led us to study the influence of multiple N-methylation of the peptide backbone on its conformation and bioactivity.[11, 12]Inspired by the bioavailability of the highly N-methylated transplantation drug cyclosporin A, which can be administered orally although it violates all Lipinski s rules on oral bioavailability;[13] we assumed this bioavailability was a result of its multiple N-methylation together with cyclization. Thus, it is possible to overcome the above mentioned bioavailability drawbacks of peptides providing both the biological activity and the receptor selectivity by multiple N-methylation of cyclic peptides. Hence, we planned to screen a complete library of all the possible N-methylated analogues of the Veber–Hirschmann cyclic hexapeptide cyclo (-PFwKTF-)(1; Figure 1) which was reported to be selective towards sst2 and