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

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.