Reevaluating the Substrate Specificity of the L-Type Amino Acid Transporter (LAT1)

Huan Chieh Chien, Claire Colas, Karissa Finke, Seth Springer, Laura Stoner, Arik A. Zur, Brooklynn Venteicher, Jerome Campbell, Colton Hall, Andrew Flint, Evan Augustyn, Christopher Hernandez, Nathan Heeren, Logan Hansen, Abby Anthony, Justine Bauer, Dimitrios Fotiadis, Avner Schlessinger, Kathleen M. Giacomini, Allen A. Thomas

Research output: Contribution to journalArticlepeer-review

51 Scopus citations


The L-type amino acid transporter 1 (LAT1, SLC7A5) transports essential amino acids across the blood-brain barrier (BBB) and into cancer cells. To utilize LAT1 for drug delivery, potent amino acid promoieties are desired, as prodrugs must compete with millimolar concentrations of endogenous amino acids. To better understand ligand-transporter interactions that could improve potency, we developed structural LAT1 models to guide the design of substituted analogues of phenylalanine and histidine. Furthermore, we evaluated the structure-activity relationship (SAR) for both enantiomers of naturally occurring LAT1 substrates. Analogues were tested in cis-inhibition and trans-stimulation cell assays to determine potency and uptake rate. Surprisingly, LAT1 can transport amino acid-like substrates with wide-ranging polarities including those containing ionizable substituents. Additionally, the rate of LAT1 transport was generally nonstereoselective even though enantiomers likely exhibit different binding modes. Our findings have broad implications to the development of new treatments for brain disorders and cancer.

Original languageEnglish
Pages (from-to)7358-7373
Number of pages16
JournalJournal of Medicinal Chemistry
Issue number16
StatePublished - 23 Aug 2018


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