Reevaluating the Substrate Specificity of the L-Type Amino Acid Transporter (LAT1)

Huan Chieh Chien, Claire Colas, Karissa Finke, Seth Springer, Laura Stoner, Arik A. Zur, Brooklynn Venteicher, Jerome Campbell, Colton Hall, Andrew Flint, Evan Augustyn, Christopher Hernandez, Nathan Heeren, Logan Hansen, Abby Anthony, Justine Bauer, Dimitrios Fotiadis, Avner Schlessinger, Kathleen M. Giacomini, Allen A Thomas

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

The L-type amino acid transporter 1 (LAT1, SLC7A5) transports essential amino acids across the blood-brain barrier (BBB) and into cancer cells. To utilize LAT1 for drug delivery, potent amino acid promoieties are desired, as prodrugs must compete with millimolar concentrations of endogenous amino acids. To better understand ligand-transporter interactions that could improve potency, we developed structural LAT1 models to guide the design of substituted analogues of phenylalanine and histidine. Furthermore, we evaluated the structure-activity relationship (SAR) for both enantiomers of naturally occurring LAT1 substrates. Analogues were tested in cis-inhibition and trans-stimulation cell assays to determine potency and uptake rate. Surprisingly, LAT1 can transport amino acid-like substrates with wide-ranging polarities including those containing ionizable substituents. Additionally, the rate of LAT1 transport was generally nonstereoselective even though enantiomers likely exhibit different binding modes. Our findings have broad implications to the development of new treatments for brain disorders and cancer.

Original languageEnglish (US)
Pages (from-to)7358-7373
Number of pages16
JournalJournal of Medicinal Chemistry
Volume61
Issue number16
DOIs
StatePublished - Aug 23 2018

Fingerprint

Amino Acid Transport Systems
Substrate Specificity
Amino Acids
Large Neutral Amino Acid-Transporter 1
Essential Amino Acids
Structural Models
Prodrugs
Brain Diseases
Structure-Activity Relationship
Blood-Brain Barrier
Phenylalanine
Histidine
Brain Neoplasms
Ligands
Pharmaceutical Preparations
Neoplasms

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Reevaluating the Substrate Specificity of the L-Type Amino Acid Transporter (LAT1). / Chien, Huan Chieh; Colas, Claire; Finke, Karissa; Springer, Seth; Stoner, Laura; Zur, Arik A.; Venteicher, Brooklynn; Campbell, Jerome; Hall, Colton; Flint, Andrew; Augustyn, Evan; Hernandez, Christopher; Heeren, Nathan; Hansen, Logan; Anthony, Abby; Bauer, Justine; Fotiadis, Dimitrios; Schlessinger, Avner; Giacomini, Kathleen M.; Thomas, Allen A.

In: Journal of Medicinal Chemistry, Vol. 61, No. 16, 23.08.2018, p. 7358-7373.

Research output: Contribution to journalArticle

Chien, HC, Colas, C, Finke, K, Springer, S, Stoner, L, Zur, AA, Venteicher, B, Campbell, J, Hall, C, Flint, A, Augustyn, E, Hernandez, C, Heeren, N, Hansen, L, Anthony, A, Bauer, J, Fotiadis, D, Schlessinger, A, Giacomini, KM & Thomas, AA 2018, 'Reevaluating the Substrate Specificity of the L-Type Amino Acid Transporter (LAT1)', Journal of Medicinal Chemistry, vol. 61, no. 16, pp. 7358-7373. https://doi.org/10.1021/acs.jmedchem.8b01007
Chien, Huan Chieh ; Colas, Claire ; Finke, Karissa ; Springer, Seth ; Stoner, Laura ; Zur, Arik A. ; Venteicher, Brooklynn ; Campbell, Jerome ; Hall, Colton ; Flint, Andrew ; Augustyn, Evan ; Hernandez, Christopher ; Heeren, Nathan ; Hansen, Logan ; Anthony, Abby ; Bauer, Justine ; Fotiadis, Dimitrios ; Schlessinger, Avner ; Giacomini, Kathleen M. ; Thomas, Allen A. / Reevaluating the Substrate Specificity of the L-Type Amino Acid Transporter (LAT1). In: Journal of Medicinal Chemistry. 2018 ; Vol. 61, No. 16. pp. 7358-7373.
@article{6adc5d6a26804a419e6b8acf9378afe4,
title = "Reevaluating the Substrate Specificity of the L-Type Amino Acid Transporter (LAT1)",
abstract = "The L-type amino acid transporter 1 (LAT1, SLC7A5) transports essential amino acids across the blood-brain barrier (BBB) and into cancer cells. To utilize LAT1 for drug delivery, potent amino acid promoieties are desired, as prodrugs must compete with millimolar concentrations of endogenous amino acids. To better understand ligand-transporter interactions that could improve potency, we developed structural LAT1 models to guide the design of substituted analogues of phenylalanine and histidine. Furthermore, we evaluated the structure-activity relationship (SAR) for both enantiomers of naturally occurring LAT1 substrates. Analogues were tested in cis-inhibition and trans-stimulation cell assays to determine potency and uptake rate. Surprisingly, LAT1 can transport amino acid-like substrates with wide-ranging polarities including those containing ionizable substituents. Additionally, the rate of LAT1 transport was generally nonstereoselective even though enantiomers likely exhibit different binding modes. Our findings have broad implications to the development of new treatments for brain disorders and cancer.",
author = "Chien, {Huan Chieh} and Claire Colas and Karissa Finke and Seth Springer and Laura Stoner and Zur, {Arik A.} and Brooklynn Venteicher and Jerome Campbell and Colton Hall and Andrew Flint and Evan Augustyn and Christopher Hernandez and Nathan Heeren and Logan Hansen and Abby Anthony and Justine Bauer and Dimitrios Fotiadis and Avner Schlessinger and Giacomini, {Kathleen M.} and Thomas, {Allen A}",
year = "2018",
month = "8",
day = "23",
doi = "10.1021/acs.jmedchem.8b01007",
language = "English (US)",
volume = "61",
pages = "7358--7373",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "16",

}

TY - JOUR

T1 - Reevaluating the Substrate Specificity of the L-Type Amino Acid Transporter (LAT1)

AU - Chien, Huan Chieh

AU - Colas, Claire

AU - Finke, Karissa

AU - Springer, Seth

AU - Stoner, Laura

AU - Zur, Arik A.

AU - Venteicher, Brooklynn

AU - Campbell, Jerome

AU - Hall, Colton

AU - Flint, Andrew

AU - Augustyn, Evan

AU - Hernandez, Christopher

AU - Heeren, Nathan

AU - Hansen, Logan

AU - Anthony, Abby

AU - Bauer, Justine

AU - Fotiadis, Dimitrios

AU - Schlessinger, Avner

AU - Giacomini, Kathleen M.

AU - Thomas, Allen A

PY - 2018/8/23

Y1 - 2018/8/23

N2 - The L-type amino acid transporter 1 (LAT1, SLC7A5) transports essential amino acids across the blood-brain barrier (BBB) and into cancer cells. To utilize LAT1 for drug delivery, potent amino acid promoieties are desired, as prodrugs must compete with millimolar concentrations of endogenous amino acids. To better understand ligand-transporter interactions that could improve potency, we developed structural LAT1 models to guide the design of substituted analogues of phenylalanine and histidine. Furthermore, we evaluated the structure-activity relationship (SAR) for both enantiomers of naturally occurring LAT1 substrates. Analogues were tested in cis-inhibition and trans-stimulation cell assays to determine potency and uptake rate. Surprisingly, LAT1 can transport amino acid-like substrates with wide-ranging polarities including those containing ionizable substituents. Additionally, the rate of LAT1 transport was generally nonstereoselective even though enantiomers likely exhibit different binding modes. Our findings have broad implications to the development of new treatments for brain disorders and cancer.

AB - The L-type amino acid transporter 1 (LAT1, SLC7A5) transports essential amino acids across the blood-brain barrier (BBB) and into cancer cells. To utilize LAT1 for drug delivery, potent amino acid promoieties are desired, as prodrugs must compete with millimolar concentrations of endogenous amino acids. To better understand ligand-transporter interactions that could improve potency, we developed structural LAT1 models to guide the design of substituted analogues of phenylalanine and histidine. Furthermore, we evaluated the structure-activity relationship (SAR) for both enantiomers of naturally occurring LAT1 substrates. Analogues were tested in cis-inhibition and trans-stimulation cell assays to determine potency and uptake rate. Surprisingly, LAT1 can transport amino acid-like substrates with wide-ranging polarities including those containing ionizable substituents. Additionally, the rate of LAT1 transport was generally nonstereoselective even though enantiomers likely exhibit different binding modes. Our findings have broad implications to the development of new treatments for brain disorders and cancer.

UR - http://www.scopus.com/inward/record.url?scp=85050865781&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85050865781&partnerID=8YFLogxK

U2 - 10.1021/acs.jmedchem.8b01007

DO - 10.1021/acs.jmedchem.8b01007

M3 - Article

C2 - 30048132

AN - SCOPUS:85050865781

VL - 61

SP - 7358

EP - 7373

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 16

ER -