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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 |
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| Authors: | Brooklynn Venteicher Kasey Merklin Dr Huy X Ngo Dr Huan-Chieh Chien Keino Hutchinson Jerome Campbell Hannah Way Joseph Griffith Cesar Alvarado Prof Surabhi Chandra Prof Evan Hill Prof Avner Schlessinger Prof Allen A Thomas |
| Affiliation: | 1. Department of Chemistry, University of Nebraska at Kearney, 2401 11th Ave, Bruner Hall of Science, Kearney, NE 68849 USA
These authors contributed equally to this work.;2. Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, 1550 4th St, Rm RH581, San Francisco, CA 94143 USA These authors contributed equally to this work.;3. Department of Pharmacological Sciences, Icahn School of Medicine at Mt. Sinai, 1468 Madison Ave, Annenberg Building Floor 19, New York, NY 10029 USA These authors contributed equally to this work.;4. Department of Chemistry, University of Nebraska at Kearney, 2401 11th Ave, Bruner Hall of Science, Kearney, NE 68849 USA;5. Department of Biology, University of Nebraska at Kearney, 2401 11th Ave, Bruner Hall of Science, Kearney, NE 68849 USA;6. Department of Psychology, University of Nebraska, at Kearney 2507 11th Ave, Copeland Hall, Kearney, NE, 68849 (USA);7. Department of Pharmacological Sciences, Icahn School of Medicine at Mt. Sinai, 1468 Madison Ave, Annenberg Building Floor 19, New York, NY 10029 USA |
| 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. |
| Keywords: | amino acids blood-brain barrier drug delivery membrane proteins prodrugs |