Testing the conformational hypothesis of passive membrane permeability using synthetic cyclic peptide diastereomers
Testing the conformational hypothesis of passive membrane permeability using synthetic cyclic peptide diastereomers
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DOI：
10.1021/ja0563455
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发表时间：
2006-03-01
影响因子：
15
通讯作者：
Lokey, RS
中科院分区：
文献类型：
--
作者：
Rezai, T;Yu, B;Lokey, RS
关于构象对小分子被动膜扩散速率的影响知之甚少。有证据表明，分子内氢键可能通过降低氢键供体（尤其是酰胺 NH 基团）去溶剂化的能量成本来发挥作用。我们开始通过研究一系列基于环[Leu-Leu-Leu-Leu-Pro-Tyr]序列的环肽非对映体的被动膜扩散特性来检验这一假设。我们根据该序列鉴定了两种环状六肽非对映异构体，其膜扩散速率相差近两个对数单位。溶液核磁共振研究和氢/氘 (H/D) 交换实验的结果表明，膜扩散速率与分子内氢键程度和 H/D 交换速率相关。渗透性最强的非对映异构体环[d-Leu-d-Leu-Leu-d-Leu-Pro-Tyr] (1) 表现出与口服药物环孢菌素 A 相当的被动膜扩散速率。
Little is known about the effect of conformation on passive membrane diffusion rates in small molecules. Evidence suggests that intramolecular hydrogen bonding may play a role by reducing the energetic cost of desolvating hydrogen bond donors, especially amide N−H groups. We set out to test this hypothesis by investigating the passive membrane diffusion characteristics of a series of cyclic peptide diastereomers based on the sequence cyclo[Leu-Leu-Leu-Leu-Pro-Tyr]. We identified two cyclic hexapeptide diastereomers based on this sequence, whose membrane diffusion rates differed by nearly two log units. Results of solution NMR studies and hydrogen/deuterium (H/D) exchange experiments showed that membrane diffusion rates correlated with the degree of intramolecular hydrogen bonding and H/D exchange rates. The most permeable diastereomer, cyclo[d-Leu-d-Leu-Leu-d-Leu-Pro-Tyr] (1), exhibited a passive membrane diffusion rate comparable to that of the orally available drug cyclosporine A.