L-Type Amino Acid Transporter 1-Utilizing Prodrugs of Ketoprofen Can Efficiently Reduce Brain Prostaglandin Levels

Montaser, Ahmed; Lehtonen, Marko; Gynther, Mikko; Huttunen, Kristiina M.

doi:10.3390/pharmaceutics12040344

Cited by 10 publications

(2 citation statements)

References 41 publications

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“…For known LAT1 substrates (L-DOPA, L-tryptophan, melphalan, gabapentin, and inhibitor BCH) as well as for studied compounds 1–12 , sample preparation and analysis were carried out like described previously. ,− Shortly, for L-tryptophan, melphalan, and compounds 2 and 4–12 , cells were lysed with 0.1 M NaOH, and an aliquot was diluted with acidified acetonitrile (0.1% formic acid) 1:4 including the internal standard (IS) diclofenac. After protein precipitation, the samples were centrifuged for 10 min with 10,000 g at 4 °C.…”

Section: Experimental Sectionmentioning

confidence: 99%

Structural Features Affecting the Interactions and Transportability of LAT1-Targeted Phenylalanine Drug Conjugates

et al. 2022

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L-type amino acid transporter 1 (LAT1) transfers essential amino acids across cell membranes. Owing to its predominant expression in the blood−brain barrier and tumor cells, LAT1 has been exploited for drug delivery and targeting to the central nervous system (CNS) and various cancers. Although the interactions of amino acids and their mimicking compounds with LAT1 have been extensively investigated, the specific structural features for an optimal drug scaffold have not yet been determined. Here, we evaluated a series of LAT1-targeted drugphenylalanine conjugates (ligands) by determining their uptake rates by in vitro studies and investigating their interaction with LAT1 via induced-fit docking. Combining the experimental and computational data, we concluded that although LAT1 can accommodate various types of structures, smaller compounds are preferred. As the ligand size increased, its flexibility became more crucial in determining the compound's transportability and interactions. Compounds with linear or planar structures exhibited reduced uptake; those with rigid lipophilic structures lacked interactions and likely utilized other transport mechanisms for cellular entry. Introducing polar groups between aromatic structures enhanced interactions. Interestingly, compounds with a carbamate bond in the aromatic ring's para-position displayed very good transport efficiencies for the larger compounds. Compared to the ester bond, the corresponding amide bond had superior hydrogen bond acceptor properties and increased interactions. A reverse amide bond was less favorable than a direct amide bond for interactions with LAT1. The present information can be applied broadly to design appropriate CNS or antineoplastic drug candidates with a prodrug strategy and to discover novel LAT1 inhibitors used either as direct or adjuvant cancer therapy.

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Section: Experimental Sectionmentioning

confidence: 99%

Structural Features Affecting the Interactions and Transportability of LAT1-Targeted Phenylalanine Drug Conjugates

et al. 2022

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“…These necessarily involve transporters, although their identity is not always known. Several recent examples showing high efficacy are based on the SLC7A5 (LAT1) transporter [ 319 , 320 , 321 , 322 , 323 , 324 ]. In one recent instance [ 321 ], the uptake of the anti-inflammatory salicylic acid was enhanced more than five-fold by fusing it with a phenylalanine moiety.…”

Section: Introductionmentioning

confidence: 99%

The Transporter-Mediated Cellular Uptake and Efflux of Pharmaceutical Drugs and Biotechnology Products: How and Why Phospholipid Bilayer Transport Is Negligible in Real Biomembranes

Kell

2021

Molecules

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Over the years, my colleagues and I have come to realise that the likelihood of pharmaceutical drugs being able to diffuse through whatever unhindered phospholipid bilayer may exist in intact biological membranes in vivo is vanishingly low. This is because (i) most real biomembranes are mostly protein, not lipid, (ii) unlike purely lipid bilayers that can form transient aqueous channels, the high concentrations of proteins serve to stop such activity, (iii) natural evolution long ago selected against transport methods that just let any undesirable products enter a cell, (iv) transporters have now been identified for all kinds of molecules (even water) that were once thought not to require them, (v) many experiments show a massive variation in the uptake of drugs between different cells, tissues, and organisms, that cannot be explained if lipid bilayer transport is significant or if efflux were the only differentiator, and (vi) many experiments that manipulate the expression level of individual transporters as an independent variable demonstrate their role in drug and nutrient uptake (including in cytotoxicity or adverse drug reactions). This makes such transporters valuable both as a means of targeting drugs (not least anti-infectives) to selected cells or tissues and also as drug targets. The same considerations apply to the exploitation of substrate uptake and product efflux transporters in biotechnology. We are also beginning to recognise that transporters are more promiscuous, and antiporter activity is much more widespread, than had been realised, and that such processes are adaptive (i.e., were selected by natural evolution). The purpose of the present review is to summarise the above, and to rehearse and update readers on recent developments. These developments lead us to retain and indeed to strengthen our contention that for transmembrane pharmaceutical drug transport “phospholipid bilayer transport is negligible”.

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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

et al. 2020

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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.

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L-Type Amino Acid Transporter 1-Utilizing Prodrugs of Ketoprofen Can Efficiently Reduce Brain Prostaglandin Levels

Cited by 10 publications

References 41 publications

Structural Features Affecting the Interactions and Transportability of LAT1-Targeted Phenylalanine Drug Conjugates

Structural Features Affecting the Interactions and Transportability of LAT1-Targeted Phenylalanine Drug Conjugates

The Transporter-Mediated Cellular Uptake and Efflux of Pharmaceutical Drugs and Biotechnology Products: How and Why Phospholipid Bilayer Transport Is Negligible in Real Biomembranes

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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