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The Effects of Prodrug Size and a Carbonyl Linker on l ‐Type Amino Acid Transporter 1‐Targeted Cellular and Brain Uptake
Author(s) -
Venteicher Brooklynn,
Merklin Kasey,
Ngo Huy X.,
Chien HuanChieh,
Hutchinson Keino,
Campbell Jerome,
Way Hannah,
Griffith Joseph,
Alvarado Cesar,
Chandra Surabhi,
Hill Evan,
Schlessinger Avner,
Thomas Allen A.
Publication year - 2021
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.202000824
Subject(s) - prodrug , amino acid , chemistry , phenylalanine , tyrosine , moiety , transporter , biochemistry , linker , aromatic amino acids , stereochemistry , computer science , gene , operating system
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.