Recent Publications

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Biophysical Journal, 2022
The human L-type amino acid transporter 1 (LAT1; SLC7A5) is a membrane transporter of amino acids, thyroid hormones, and drugs such as the Parkinson’s disease drug levodopa (L-Dopa). LAT1 is found in the blood-brain barrier, testis, bone marrow, and placenta, and its dysregulation has been associated with various neurological diseases, such as autism and epilepsy, as well as cancer. In this study, we combine metainference molecular dynamics simulations, molecular docking, and experimental testing, to characterize LAT1-inhibitor interactions. We first conducted a series of molecular docking experiments to identify the most relevant interactions between LAT1’s substrate-binding site and ligands, including both inhibitors and substrates. We then performed metainference molecular dynamics simulations using cryoelectron microscopy structures in different conformations of LAT1 with the electron density map as a spatial restraint, to explore the inherent heterogeneity in the structures. We analyzed the LAT1 substrate-binding site to map important LAT1-ligand interactions as well as newly described druggable pockets. Finally, this analysis guided the discovery of previously unknown LAT1 ligands using virtual screening and cellular uptake experiments. Our results improve our understanding  of LAT1-inhibitor recognition, providing a framework for rational design of future lead compounds targeting this key drug target.  

Nucleosides, Nucleotides & Nucleic Acids, 2022
We report the synthesis and cytotoxicity in MCF-7 and MDA-MB-231 breast  cancer cells of novel 1,2,3- and 1,2,4-triazolyl analogs of ribavirin.  We modified ribavirin’s carboxamide moiety to test the effects of  lipophilic groups. 1-β-D-Ribofuranosyl-1H-1,2,3-triazoles were  prepared using Click Chemistry, whereas an unprecedented application of a  prior 1,2,4-triazole ring synthesis was used for 1-β-D-ribofuranosyl-1H-1,2,4-triazole  analogs. Though cytotoxicity was mediocre and there was no correlation  with lipophilicity, we discovered that a structurally similar  concentrative nucleoside transporter 2 (CNT2) inhibitor was modestly  cytotoxic (MCF-7 IC50 of 42 µM). These syntheses could be used to efficiently investigate variation in the nucleobase. 

ChemMedChem, 2021

 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 it 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 analogs.  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 (BBB) or  on cancer cells. 

Bioorganic and Medicinal Chemistry Letters, 2019

A series of 1,2,3-triazole analogs of the amino acids L-histidine and  L-tryptophan were modeled, synthesized and tested for L-type amino acid  transporter 1 (LAT1; SLC7A5) activity to guide the design of amino  acid-drug conjugates (prodrugs). These triazoles were conveniently  prepared by the highly convergent Huisgen 1,3-dipolar cycloaddition  (Click Chemistry). Despite comparable predicted binding modes, triazoles  generally demonstrated reduced cell uptake and LAT1 binding potency  relative to their natural amino acid counterparts. The  structure-activity relationship (SAR) data for these triazoles has  important ramifications for treating cancer and brain disorders using  amino acid prodrugs or LAT1 inhibitors. 

Journal of Medicinal Chemistry 2018, 61, 7358-73.

 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. 

https://orcid.org/0000-0001-8313-0879