Intestinal Permeability of Cyclic Peptides: Common Key Backbone Motifs Identified
Intestinal Permeability of Cyclic Peptides: Common Key Backbone Motifs Identified
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DOI：
10.1021/ja303200d
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发表时间：
2012-07-25
影响因子：
15
通讯作者：
Kessler, Horst
中科院分区：
文献类型：
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作者：
Beck, Johannes G.;Chatterjee, Jayanta;Kessler, Horst
口服生物利用度不足被认为是广泛开发肽作为治疗剂的关键限制。虽然小分子有机化合物的口服生物利用度通常是根据简单的规则来估计的，但类似的规则不适用于肽，甚至对少数肽所描述的高口服生物利用度也没有很好的理解。在这里，我们提出了两个高度Caco-2渗透的模板结构的基础上的54个环（-D-Ala-Ala（5）-）肽与不同的N-甲基化模式的库。第一个（全反式）模板结构具有沿沿着Ala（6）-D-Ala（1）和Ala（3）-Ala（4）的两个II型β转角，并且仅在D-Ala（1）和Ala（6）处具有两个N-甲基的一种肽中发现[（NMe（1，6）]。第二个（单顺式）模板在Ala（5）之前具有特征性顺式肽键，这导致沿着Ala（4）-Ala（5）的VI型β-转角几何结构沿着。虽然在Ala（5）上携带N-甲基的七种肽中发现了第二模板结构，但仅在其中两种[NMe（1，5）和NMe（1，2，4，5）]的亚组中发现了高Caco-2渗透性，这表明D-Ala（1）的N-甲基化是第二模板结构高渗透性的先决条件。第二模板结构与口服生物可利用的生长抑素类似物环（-Pro-Phe-NMe-D-Trp-NMe-Lys-Thr-NMe-Phe-）的结构相似性，以及与口服生物可利用的肽环孢菌素A的两个β-转角的惊人相似性，表明在高度Caco-2渗透性模板上引入生物活性序列可以产生有效的口服生物可利用的候选药物。
Insufficient oral bioavailability is considered as a key limitation for the widespread development of peptides as therapeutics. While the oral bioavailability of small organic compounds is often estimated from simple rules, similar rules do not apply to peptides, and even the high oral bioavailability that is described for a small number of peptides is not well understood. Here we present two highly Caco-2 permeable template structures based on a library of 54 cyclo(-D-Ala-Ala(5)-) peptides with different N-methylation patterns. The first (all-trans) template structure possesses two beta-turns of type II along Ala(6)-D-Ala(1) and Ala(3)-Ala(4) and is only found for one peptide with two N-methyl groups at D-Ala(1) and Ala(6) [(NMe(1,6)]. The second (single-cis) template possesses a characteristic cis peptide bond preceding Ala(5), which results in type VI beta-turn geometry along Ala(4)-Ala(5). Although the second template structure is found in seven peptides carrying N-methyl groups on Ala(5), high Caco-2 permeability is only found for a subgroup of two of them [NMe(1,5) and NMe(1,2,4,5)], suggesting that N-methylation of D-Ala(1) is a prerequisite for high permeability of the second template structure. The structural similarity of the second template structure with the orally bioavailable somatostatin analog cyclo(-Pro-Phe-NMe-D-Trp-NMe-Lys-Thr-NMe-Phe-), and the striking resemblance with both beta-turns of the orally bioavailable peptide cyclosporine A, suggests that the introduction of bioactive sequences on the highly Caco-2 permeable templates may result in potent orally bioavailable drug candidates.