159490-55-8Relevant articles and documents
The Effects of Prodrug Size and a Carbonyl Linker on l-Type Amino Acid Transporter 1-Targeted Cellular and Brain Uptake
Venteicher, Brooklynn,Merklin, Kasey,Ngo, Huy X.,Chien, Huan-Chieh,Hutchinson, Keino,Campbell, Jerome,Way, Hannah,Griffith, Joseph,Alvarado, Cesar,Chandra, Surabhi,Hill, Evan,Schlessinger, Avner,Thomas, Allen A.
supporting information, p. 869 - 880 (2020/12/15)
The l-type amino acid transporter 1 (LAT1, SLC7A5) imports dietary amino acids and amino acid drugs (e. g., l-DOPA) into the brain, and plays a role in cancer metabolism. Though there have been numerous reports of LAT1-targeted amino acid-drug conjugates (prodrugs), identifying the structural determinants to enhance substrate activity has been challenging. In this work, we investigated the position and orientation of a carbonyl group in linking hydrophobic moieties including the anti-inflammatory drug ketoprofen to l-tyrosine and l-phenylalanine. We found that esters of meta-carboxyl l-phenylalanine had better LAT1 transport rates than the corresponding acylated l-tyrosine analogues. However, as the size of the hydrophobic moiety increased, we observed a decrease in LAT1 transport rate with a concomitant increase in potency of inhibition. Our results have important implications for designing amino acid prodrugs that target LAT1 at the blood-brain barrier or on cancer cells.
