Because of the formidable barrier function of the endothelial cells that line the blood-brain barrier (BBB), targeting drugs to the brain represents an enormous challenge for drug developers. Recent studies suggest that influx transporters may be targeted for enhanced drug delivery. The membrane transporter SLC7A5, also known as the “L-Type” or “Large Neutral” Amino Acid Transporter 1 (LAT1), is highly expressed at the BBB and in cancer cells. Because of its high expression level in the BBB, and its role in transporting essential amino acids to the brain and cancer cells, LAT1 represents an attractive target for drug delivery. We and others have been trying to optimize ligand affinity for the purposes of preparing more effective amino acid-containing prodrugs, and alternatively to obtain potent LAT1 inhibitors for blocking cancer cell metabolism. Guided by computational modeling, we have prepared or purchased various non-natural amino acid analogs, including substitution at different positions, modification of the carboxylic acid functional group, and D isomers of endogenous LAT1 substrates. We assessed transport activity using both <i>cis</i>-inhibition and <i>trans</i>-stimulation assays in HEK cells with inducible LAT1 expression. Surprisingly, we have found that LAT1 transports a variety of D amino acids as well as phenylalanine analogs containing functional groups that would be charged at physiologic pH (carboxylic acid and amino substituents). Moreover, we have found that LAT1 can also transport carboxylic acid bioisosteres (hydroxamic acids and esters). Our findings suggest that LAT1 is remarkably promiscuous, as it transports a variety of D and L amino acids, and it is not limited to transporting “neutral” or even “amino acid” containing ligands. The presented SAR has broad implications for how to design better LAT1 substrates and inhibitors that could be beneficial for treating brain disorders and cancer.

LAT1 membrane transporter: reevaluating the meaning of L and A

255th National Meeting (2018)

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