Structural properties for selective and efficient l-type amino acid transporter 1 (LAT1) mediated cellular uptake

Publication date: 10 June 2018 Source:International Journal of Pharmaceutics, Volume 544, Issue 1 Author(s): Jussi Kärkkäinen, Mikko Gynther, Tarja Kokkola, Aleksanteri Petsalo, Seppo Auriola, Maija Lahtela-Kakkonen, Krista Laine, Jarkko Rautio, Kristiina M. Huttunen l-Type amino acid transporter 1 (LAT1) is a sodium-independent exchanger transporting large neural amino acids and several amino-acid mimicking drugs across the cell membranes. LAT1 is highly expressed at the blood brain barrier (BBB) and in numerous cancer cells and is therefore a potential drug target. However, structural features affecting the ability to bind to LAT1 and the cellular translocation by LAT1 are unclear. In the present study we determined the binding to and transport through human LAT1 of several compounds into the human breast adenocarcinoma cells (MCF-7). We show that the meta-conjugation of l-phenylalanine increases binding to human LAT1 compared to para-conjugation or aliphatic amino acid moiety. Furthermore, large, rigid and aromatic meta-substituted l-phenylalanine derivative enabled selective and efficient LAT1-mediated cellular uptake. Our results also demonstrates that in addition to binding studies, it is of utmost importance to determine the cellular accumulation of compounds. It provides crucial information on transport efficiency and selectivity of transport mechanisms that the compounds are able to utilize. Overall, these structural findings and the methodology used her...
Source: International Journal of Pharmaceutics - Category: Drugs & Pharmacology Source Type: research