The l‐type amino acid transporter 1 (LAT1, SLC7A5) imports dietary amino acids and amino acid drugs (e. g., l‐DOPA) into the brain, and plays a role in cancer metabolism. Though there have been numerous reports of LAT1‐targeted amino acid‐drug conjugates (prodrugs), identifying the structural determinants to enhance substrate activity has been challenging. In this work, we investigated the position and orientation of a carbonyl group in linking hydrophobic moieties including the anti‐inflammatory drug ketoprofen to l‐tyrosine and l‐phenylalanine. We found that esters of meta‐carboxyl l‐phenylalanine had better LAT1 transport rates than the corresponding acylated l‐tyrosine analogues. However, as the size of the hydrophobic moiety increased, we observed a decrease in LAT1 transport rate with a concomitant increase in potency of inhibition. Our results have important implications for designing amino acid prodrugs that target LAT1 at the blood‐brain barrier or on cancer cells.

中文翻译：

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前药大小和羰基接头对 l 型氨基酸转运蛋白 1 靶向细胞和脑摄取的影响

l型氨基酸转运蛋白 1（LAT1，SLC7A5）将膳食氨基酸和氨基酸药物（例如l - DOPA）输入大脑，并在癌症代谢中发挥作用。尽管有大量关于 LAT1 靶向氨基酸药物偶联物（前药）的报道，但确定结构决定因素以增强底物活性一直具有挑战性。在这项工作中，我们研究了羰基在连接疏水部分（包括抗炎药酮洛芬）与l-酪氨酸和l-苯丙氨酸时的位置和方向。我们发现间羧基l-苯丙氨酸酯比相应的酰化l-苯丙氨酸酯具有更好的 LAT1 转运速率。-酪氨酸类似物。然而，随着疏水部分的大小增加，我们观察到 LAT1 转运速率降低，同时抑制效力增加。我们的结果对于设计靶向血脑屏障或癌细胞上的 LAT1 的氨基酸前药具有重要意义。