Enantiomeric Cyclic Peptides with Different Caco-2 Permeability Suggest Carrier-Mediated Transport
Enantiomeric Cyclic Peptides with Different Caco-2 Permeability Suggest Carrier-Mediated Transport
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DOI：
10.1002/chem.201501270
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发表时间：
2015-05-26
影响因子：
4.3
通讯作者：
Kessler, Horst
中科院分区：
文献类型：
--
作者：
Marelli, Udaya Kiran;Bezencon, Jacqueline;Kessler, Horst
最近，环六肽的口服吸收通过其骨架酰胺的N-甲基化来改善。然而，在Caco-2模型中测量的N-甲基化或溶剂暴露的NH的数量和位置与肠通透性无关。在这项研究中，我们调查对映体对三个极性和两个亲脂性肽，以证明载体介导的转运蛋白的参与。正如预期的那样，所有对映体肽表现出相同的亲脂性（logD（7.4））和被动跨细胞渗透性测定的平行人工膜渗透性测定（PAMPA）。然而，对映体极性肽在a-b和b-a两个方向上表现出不同的Caco-2渗透性（P-app）。对于亲脂性肽之一观察到相同的趋势，而第二亲脂性对映异构体对显示出相同的Caco-2渗透性（在误差内）。这些发现提供了参与载体介导的肽，特别是极性性质的肽的运输的第一个证据。
Recently, oral absorption of cyclic hexapeptides was improved by N-methylation of their backbone amides. However, the number and position of N-methylations or of solvent exposed NHs did not correlate to intestinal permeability, measured in a Caco-2 model. In this study, we investigate enantiomeric pairs of three polar and two lipophilic peptides to demonstrate the participation of carrier-mediated transporters. As expected, all the enantiomeric peptides exhibited identical lipophilicity (logD(7.4)) and passive transcellular permeability determined by the parallel artificial membrane permeability assay (PAMPA). However, the enantiomeric polar peptides exhibited different Caco-2 permeability (P-app) in both directions a-b and b-a. The same trend was observed for one of the lipophilic peptide, whereas the second lipophilic enantiomer pair showed identical Caco-2 permeability (within the errors). These findings provide the first evidence for the involvement of carrier-mediated transport for peptides, especially for those of polar nature.