The Effects of Prodrug Size and a Carbonyl Linker on l-Type Amino Acid Transporter 1-Targeted Cellular and Brain Uptake

Brooklynn Venteicher, Kasey Merklin, Huy X. Ngo, Huan Chieh Chien, Keino Hutchinson, Jerome Campbell, Hannah Way, Joseph Griffith, Cesar Alvarado, Surabhi Chandra, Evan Hill, Avner Schlessinger, Allen A. Thomas

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)869-880
Number of pages12
JournalChemMedChem
Volume16
Issue number5
DOIs
StatePublished - Mar 3 2021

Keywords

  • amino acids
  • blood-brain barrier
  • drug delivery
  • membrane proteins
  • prodrugs

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Pharmacology
  • Drug Discovery
  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Organic Chemistry

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