Connecting the conformational behavior of cyclic octadepsipeptides with their ionophoric property and membrane permeability.
Connecting the conformational behavior of cyclic octadepsipeptides with their ionophoric property and membrane permeability.
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DOI：
10.1039/d0ob01447h
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发表时间：
2020-09-23
影响因子：
3.2
通讯作者：
Riniker S
中科院分区：
文献类型：
--
作者：
Stadelmann T;Subramanian G;Menon S;Townsend CE;Lokey RS;Ebert MO;Riniker S
环状八缩酚酸肽如PF 1022 A及其合成衍生物依莫地昔表现出驱虫活性，后者作为用于动物健康用途的针对胃肠道线虫的商业药物治疗出售。这些环状缩酚肽的结构-渗透性关系，最终可以提供洞察化合物的生物利用度尚未得到很好的理解。完全N-甲基化的酰胺骨架和非极性侧链残基不允许形成分子内氢键，通常在环肽的膜渗透构象中观察到。因此，对这些缩肽的任何理解都将作为未来设计策略的原型。在先前的核磁共振（NMR）研究中，检测到两种大环核心构象的依莫德塞，一种具有反式构型的所有骨架酰胺（在此称为对称构象），另一种具有顺式构型的一个酰胺（在此称为不对称构象）。此外，这些缩肽也被报道为离子载体，钾的偏好超过钠。在这项研究中，我们涉及PF 1022 A，emodepside，和密切相关的类似物的构象行为与他们的离子特性探测使用NMR和分子动力学（MD）模拟，并最终评估其被动膜渗透性使用PAMPA。我们发现，两个核心的构象之间的平衡更倾向于对称构象时，除了一价阳离子与钾钠的选择性。NMR实验和理论马尔可夫状态模型的基础上广泛的MD模拟表明一个更刚性的骨干的不对称构象，而对称构象显示出更大的灵活性。实验结果进一步支持了阳离子结合的对称构象。PAMPA结果表明，研究的缩肽保留在膜上，这可能是有利的可能的目标，膜结合钾通道。
Cyclic octadepsipeptides such as PF1022A and its synthetic derivative emodepside exhibit anthelmintic activity with the latter sold as a commercial drug treatment against gastrointestinal nematodes for animal health use. The structure-permeability relationship of these cyclic depsipeptides that could ultimately provide insights into the compound bioavailability is not yet well understood. The fully N-methylated amide backbone and apolar sidechain residues do not allow for the formation of intramolecular hydrogen bonds, normally observed in the membrane-permeable conformations of cyclic peptides. Hence, any understanding gained on these depsipeptides would serve as a prototype for future design strategies. In previous nuclear magnetic resonance (NMR) studies, two macrocyclic core conformers of emodepside were detected, one with all backbone amides in trans-configuration (hereon referred as the symmetric conformer) and the other with one amide in cis-configuration (hereon referred as the asymmetric conformer). In addition, these depsipeptides were also reported to be ionophores with a preference of potassium over sodium. In this study, we relate the conformational behavior of PF1022A, emodepside, and closely related analogs with their ionophoric characteristic probed using NMR and molecular dynamics (MD) simulations and finally evaluated their passive membrane permeability using PAMPA. We find that the equilibrium between the two core conformers shifts more towards the symmetric conformer upon addition of monovalent cations with selectivity for potassium over sodium. Both the NMR experiments and the theoretical Markov state models based on extensive MD simulations indicate a more rigid backbone for the asymmetric conformation, whereas the symmetric conformation shows greater flexibility. The experimental results further advocate for the symmetric conformation binding the cation. The PAMPA results suggest that the investigated depsipeptides are retained in the membrane, which may be advantageous for the likely target, a membrane-bound potassium channel.
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影响因子：
2
作者：
Harder, A;Holden-Dye, L;Wunderlich, F
通讯作者：
Wunderlich, F
影响因子：
--
作者：
Alex, Alexander;Millan, David S.;Whitlock, Gavin A.
通讯作者：
Whitlock, Gavin A.
影响因子：
2.7
作者：
Dyker, H;Harder, A;Scherkenbeck, J
通讯作者：
Scherkenbeck, J
影响因子：
7.4
作者：
Eilers, PHC
通讯作者：
Eilers, PHC
影响因子：
5.4
作者：
Andavan GS;Lemmens-Gruber R
通讯作者：
Lemmens-Gruber R