Structure-based ligand discovery for the Large-neutral Amino Acid Transporter 1, LAT-1
Structure-based ligand discovery for the Large-neutral Amino Acid Transporter 1, LAT-1
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DOI：
10.1073/pnas.1218165110
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发表时间：
2013-04-02
影响因子：
11.1
通讯作者：
Giacomini, Kathleen M.
中科院分区：
文献类型：
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作者：
Geier, Ethan G.;Schlessinger, Avner;Giacomini, Kathleen M.
大中性氨基酸转运蛋白1(LAT-1)是一种不依赖钠的氨基酸、甲状腺激素和处方药的交换器，在血脑屏障和各种癌症中高度表达。Lat-1在癌症的发展以及调节药物和营养物质跨血脑屏障的输送方面发挥着重要作用，使其成为关键的药物靶点。在这里，我们通过比较建模、虚拟筛选和实验验证确定了四个LAT-1配体，其中包括一个化学上新颖的底物。这些结果可能使包括抗癌剂阿维菌素在内的两种药物增强大脑通透性的作用合理化。最后，我们的两个HITS通过不同的机制抑制了癌细胞的增殖，为表征LAT-1在癌症代谢中的作用提供了有用的化学工具。
The Large-neutral Amino Acid Transporter 1 (LAT-1)-a sodium-independent exchanger of amino acids, thyroid hormones, and prescription drugs-is highly expressed in the blood-brain barrier and various types of cancer. LAT-1 plays an important role in cancer development as well as in mediating drug and nutrient delivery across the blood-brain barrier, making it a key drug target. Here, we identify four LAT-1 ligands, including one chemically novel substrate, by comparative modeling, virtual screening, and experimental validation. These results may rationalize the enhanced brain permeability of two drugs, including the anticancer agent acivicin. Finally, two of our hits inhibited proliferation of a cancer cell line by distinct mechanisms, providing useful chemical tools to characterize the role of LAT-1 in cancer metabolism.