@article{87d6f1d1e0024169b447b675c87c5c75,
title = "The Effects of Prodrug Size and a Carbonyl Linker on l-Type Amino Acid Transporter 1-Targeted Cellular and Brain Uptake",
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",
author = "Brooklynn Venteicher and Kasey Merklin and Ngo, {Huy X.} and Chien, {Huan Chieh} and Keino Hutchinson and Jerome Campbell and Hannah Way and Joseph Griffith and Cesar Alvarado and Surabhi Chandra and Evan Hill and Avner Schlessinger and Thomas, {Allen A.}",
note = "Funding Information: This work was supported by the National Institutes of Health's National Institute of Neurological Disorders and Stroke grant R15 NS099981 (A.A.T), the National Institutes of Health's National Institute of General Medical Sciences grant R01 GM117163 (H.N. and H.C.C.) and R01 GM108911 (A.S.) and T32 GM062754 (K.H.). We appreciate OpenEye Scientific Software Inc. for granting us access to its high‐performance molecular modeling applications through its academic license program. We are grateful to Prof. Kathleen Giacomini (UCSF) for assistance with manuscript editing and cell biology consultation. Additionally, A.A.T. and E.H. thank Prof. Janet Steele (UNK Department of Biology), Dr. Arik A. Zur (BioLineRx), Ms. Alyssa Wells (UNK student), and Prof. Howard Gendelman (UNMC Department of Pharmacology and Experimental Neuroscience) for assistance and consultation regarding rat brain perfusion experiments. Publisher Copyright: {\textcopyright} 2020 Wiley-VCH GmbH",
year = "2021",
month = mar,
day = "3",
doi = "10.1002/cmdc.202000824",
language = "English",
volume = "16",
pages = "869--880",
journal = "ChemMedChem",
issn = "1860-7179",
publisher = "John Wiley and Sons Ltd",
number = "5",
}