cis-Peptide Bonds: A Key for Intestinal Permeability of Peptides? .
cis-Peptide Bonds: A Key for Intestinal Permeability of Peptides? .
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顺式肽键：肽肠渗透性的关键？â
DOI：
10.1002/chem.201501600
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发表时间：
2015
期刊：
影响因子：
--
通讯作者：
H. Kessler
中科院分区：
文献类型：
--
作者：
U. Kiran Marelli;O. Ovadia;A. O. Frank;J. Chatterjee;C. Gilon;A. Hoffman;H. Kessler
最近对环状六肽库的结构研究导致鉴定了可能有助于肽的口服利用度的常见骨架构象。此外，观察到这些肽中的一些肽的对映体对的不同Caco-2渗透性强烈支持构象特异性驱动摄取的概念，并且还表明载体介导的肽转运途径的关键作用，特别是对于极性性质的支架。本工作研究了13个选择性的N-甲基化环状五丙氨酸肽衍生自基本环（-D-Ala-Ala 4-）模板的Caco-2和PAMPA渗透性概况。这些分子通常在肠上皮细胞中显示出中度至低度转运，其中一些分子表现出的Caco-2渗透性等于或略高于甘露醇（细胞旁渗透性的标志物）。我们发现大多数可渗透的环状五肽和六肽具有N-甲基化顺式肽键，这一结构特征也存在于口服肽环孢菌素A和Veber-Hirschmann肽的三-N-甲基化类似物中。 基于这些观察结果，在某些位置存在N-甲基化顺式-肽键可能通过合适的构象预组织促进肽的肠渗透性。
Recent structural studies on libraries of cyclic hexapeptides led to the identification of common backbone conformations that may be instrumental to the oral availability of peptides. Furthermore, the observation of differential Caco‐2 permeabilities of enantiomeric pairs of some of these peptides strongly supports the concept of conformational specificity driven uptake and also suggests a pivotal role of carrier‐mediated pathways for peptide transport, especially for scaffolds of polar nature. This work presents investigations on the Caco‐2 and PAMPA permeability profiles of 13 selectedN‐methylated cyclic pentaalanine peptides derived from the basic cyclo(‐D‐Ala‐Ala4‐) template. These molecules generally showed moderate to low transport in intestinal epithelia with a few of them exhibiting a Caco‐2 permeability equal to or slightly higher than that of mannitol, a marker for paracellular permeability. We identified that the majority of the permeable cyclic penta‐ and hexapeptides possess anN‐methylatedcis‐peptide bond, a structural feature that is also present in the orally available peptides cyclosporine A and the tri‐N‐methylated analogue of the Veber–Hirschmann peptide. Based on these observations it appears that the presence ofN‐methylatedcis‐peptide bonds at certain locations may promote the intestinal permeability of peptides through a suitable conformational preorganization.
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影响因子：
15
作者：
Beck, Johannes G.;Chatterjee, Jayanta;Kessler, Horst
通讯作者：
Kessler, Horst
影响因子：
7.3
作者：
Giordanetto, Fabrizio;Kihlberg, Jan
通讯作者：
Kihlberg, Jan
影响因子：
4.3
作者：
Marelli, Udaya Kiran;Bezencon, Jacqueline;Kessler, Horst
通讯作者：
Kessler, Horst
影响因子：
4
作者：
Bock JE;Gavenonis J;Kritzer JA
通讯作者：
Kritzer JA
影响因子：
15
作者：
Rezai, Taha;Bock, Jonathan E.;Jacobson, Matthew P.
通讯作者：
Jacobson, Matthew P.