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

Author(s)
H. C. Chien, Claire Colas, K. Finke, S. Springer, L. Stoner, A. A. Zur, B. Venteicher, J. Campbell, C. Hall, A. Flint, E. Augustyn, C. Hernandez, N. Heeren, L. Hansen, A. Anthony, J. Bauer, D. Fotiadis, Avner Schlessinger, K. M. Giacomini, A. A. Thomas
Abstract

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.

Organisation(s)
External organisation(s)
University of California, San Francisco, Icahn School of Medicine at Mount Sinai, New York, Universität Bern, University of Nebraska - Kearney
Journal
Journal of Medicinal Chemistry
Volume
61
Pages
7358-7373
ISSN
0022-2623
DOI
https://doi.org/10.1021/acs.jmedchem.8b01007
Publication date
08-2018
Peer reviewed
Yes
Austrian Fields of Science 2012
Chemical biology
Portal url
https://ucris.univie.ac.at/portal/en/publications/reevaluating-the-substrate-specificity-of-the-ltype-amino-acid-transporter-lat1(cfe1f867-0ca5-4193-8723-00e97cadeb25).html