School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland.
School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland.
Int J Pharm. 2018 Jun 10;544(1):91-99. doi: 10.1016/j.ijpharm.2018.04.025. Epub 2018 Apr 15.
l-Type amino acid transporter 1 (LAT1) is a sodium-independent exchanger transporting large neural amino acids and several amino-acid mimicking drugs across the cell membranes. LAT1 is highly expressed at the blood brain barrier (BBB) and in numerous cancer cells and is therefore a potential drug target. However, structural features affecting the ability to bind to LAT1 and the cellular translocation by LAT1 are unclear. In the present study we determined the binding to and transport through human LAT1 of several compounds into the human breast adenocarcinoma cells (MCF-7). We show that the meta-conjugation of l-phenylalanine increases binding to human LAT1 compared to para-conjugation or aliphatic amino acid moiety. Furthermore, large, rigid and aromatic meta-substituted l-phenylalanine derivative enabled selective and efficient LAT1-mediated cellular uptake. Our results also demonstrates that in addition to binding studies, it is of utmost importance to determine the cellular accumulation of compounds. It provides crucial information on transport efficiency and selectivity of transport mechanisms that the compounds are able to utilize. Overall, these structural findings and the methodology used herein are exploitable to design LAT1-utilizing compounds, such as markers for cancer imaging and drug molecules, enabling more effective and safer treatments for cancer in the future.
L 型氨基酸转运蛋白 1（LAT1）是一种不依赖于钠的交换体，可将大的神经氨基酸和几种氨基酸模拟药物穿过细胞膜。LAT1 在血脑屏障（BBB）和许多癌细胞中高度表达，因此是一个潜在的药物靶点。然而，影响与 LAT1 结合以及 LAT1 细胞转运能力的结构特征尚不清楚。在本研究中，我们确定了几种化合物与人 LAT1 的结合以及通过人 LAT1 转运到人类乳腺癌腺癌细胞（MCF-7）中的情况。我们表明，与对位共轭或脂肪族氨基酸部分相比，l-苯丙氨酸的间位共轭增加了与人 LAT1 的结合。此外，大的、刚性和芳香性的间位取代的 l-苯丙氨酸衍生物能够实现选择性和有效的 LAT1 介导的细胞摄取。我们的结果还表明，除了结合研究外，确定化合物的细胞积累也非常重要。它提供了有关化合物能够利用的转运机制的转运效率和选择性的关键信息。总的来说，这些结构发现和本文中使用的方法可用于设计利用 LAT1 的化合物，例如癌症成像的标志物和药物分子，从而为未来的癌症提供更有效和更安全的治疗方法。
