Flerin Martin, Duarte Fernanda, Langton Matthew J
Department of Chemistry, University of Oxford, Chemistry Research Laboratory, 12 Mansfield Road, Oxford, OX1 3TA, UK.
Chemistry. 2025 Aug 1;31(43):e202502033. doi: 10.1002/chem.202502033. Epub 2025 Jun 26.
Synthetic ion transporters hold promise as both chemical probes and potential therapeutics for diseases linked to malfunctioning protein ion transporters. However, their application in biological systems is limited, partly due to the cytotoxicity arising from unselective ion transport. Here, we demonstrate that highly active and selective anionophores can be accessed by combining halogen bonding anion recognition with macrocyclic anion encapsulation. Anion transport experiments in large unilamellar vesicles (LUVs) revealed over 300-fold selectivity for chloride transport over proton/hydroxide ions, which is key for potential future therapeutic applications, where the dissipation of cellular pH gradients must be avoided. The mechanism underpinning selectivity is studied through Density Functional Theory (DFT) calculations and molecular dynamics (MD) simulations at the membrane interface, demonstrating that the cyclic structure imposes an energetic preference for chloride binding over hydroxide, as well as a greater desolvation of hydroxide, which further disfavors its transport. We anticipate that these results will accelerate the transition toward the use of artificial chloride transport in biology.
合成离子转运体有望成为用于与蛋白质离子转运体功能失调相关疾病的化学探针和潜在疗法。然而，它们在生物系统中的应用受到限制，部分原因是由于非选择性离子转运产生的细胞毒性。在此，我们证明通过将卤素键阴离子识别与大环阴离子封装相结合，可以获得高活性和选择性的阴离子载体。在大单层囊泡（LUVs）中的阴离子转运实验表明，氯离子转运相对于质子/氢氧根离子具有超过300倍的选择性，这对于潜在的未来治疗应用至关重要，因为必须避免细胞pH梯度的消散。通过密度泛函理论（DFT）计算和膜界面处的分子动力学（MD）模拟研究了选择性的基础机制，表明环状结构对氯离子结合比对氢氧根具有能量偏好，以及氢氧根更大的去溶剂化作用，这进一步不利于其转运。我们预计这些结果将加速在生物学中使用人工氯离子转运的转变。
