Membrane transporters in drug development and as determinants of precision medicine

Galetin, Aleksandra; Brouwer, Kim L. R.; Tweedie, Donald; Yoshida, Kenta; Sjöstedt, Noora; Aleksunes, Lauren; Chu, Xiaoyan; Evers, Raymond; Hafey, Michael J.; Lai, Yurong; Matsson, Pär; Riselli, Andrew; Shen, Hong; Sparreboom, Alex; Varma, Manthena V. S.; Yang, Jia; Yang, Xinning; Yee, Sook Wah; Zamek-Gliszczynski, Maciej J.; Zhang, Lei; Giacomini, Kathleen M.

doi:10.1038/s41573-023-00877-1

Cited by 51 publications

(6 citation statements)

References 241 publications

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“…In this context it seems plausible that hSLC19A3 might also represent a transport route for existing and prospective medical compounds. In particular, it might be an interesting entry gate for drugs to cross the blood-brain barrier 7,49 . Our structural data provide a basis for the rational design of drugs to prevent the side effects of thiamine uptake inhibition or to use hSLC19A3 for tissue-specific drug delivery 49 .…”

Section: Discussionmentioning

confidence: 99%

“…In particular, it might be an interesting entry gate for drugs to cross the blood-brain barrier 7,49 . Our structural data provide a basis for the rational design of drugs to prevent the side effects of thiamine uptake inhibition or to use hSLC19A3 for tissue-specific drug delivery 49 . The other high-affinity thiamine transporter, hSLC19A2, shares high sequence identity (48%) 26 and, based on AF2 predictions 39 , high structural conservation with hSLC19A3 (Supplementary Fig.…”

Section: Discussionmentioning

confidence: 99%

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Structural basis of substrate transport and drug recognition by the human thiamine transporter SLC19A3

Gabriel,

Spriestersbach,

Fuhrmann

et al. 2024

Preprint

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Thiamine (vitamin B1) functions as an essential coenzyme in cells. Humans and other mammals cannot synthesise this vitamin de novo and thus have to take it up from their diet. Eventually, every cell needs to import thiamine across its plasma membrane which is mainly mediated by two specific thiamine transporters SLC19A2 and SLC19A3. Loss of function mutations in either of these transporters leads to detrimental, life-threatening metabolic disorders. SLC19A3 is furthermore a major site of drug interactions. Many medications, including antidepressants, antibiotics and chemotherapeutics are known to inhibit this transporter, with potentially fatal consequences for patients. Despite a thorough functional characterisation over the past two decades, the structural basis of its transport mechanism and drug interactions has remained elusive. Here, we report eight cryo-electron microscopy (cryo-EM) structures of the human thiamine transporter SLC19A3 in complex with various ligands. Conformation-specific nanobodies enabled us to capture different states of SLC19A3's transport cycle, revealing the molecular details of thiamine recognition and transport. We identified nine novel drug interactions of SLC19A3 and determined structures of the transporter in complex with the inhibitors fedratinib, hydroxychloroquine, amprolium and amitriptyline. These data allow us to develop an understanding of the transport mechanism and ligand recognition of SLC19A3.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Structural basis of substrate transport and drug recognition by the human thiamine transporter SLC19A3

Gabriel,

Spriestersbach,

Fuhrmann

et al. 2024

Preprint

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“…Similarly, Basic helix-loop-helix family member e40 (BHLHE40) is inversely related to ABCB1, suggesting that the upstream target of ABCB1 can be used to overcome ABCB1-mediated chemoresistance [68] . Recent research has explored the broad substrate specifity, and conversion of efflux to influx pump via engineering of ABC transporter, and the importance of membrane transporters is also highlighted in the development of precision medicine [69,70] .…”

Section: Abc Superfamily Transportersmentioning

confidence: 99%

Novel players in the development of chemoresistance in ovarian cancer: ovarian cancer stem cells, non-coding RNA and nuclear receptors

Alam,

Giri

2024

Cancer Drug Resist

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Ovarian cancer (OC) ranks as the fifth leading factor for female mortality globally, with a substantial burden of new cases and mortality recorded annually. Survival rates vary significantly based on the stage of diagnosis, with advanced stages posing significant challenges to treatment. OC is primarily categorized as epithelial, constituting approximately 90% of cases, and correct staging is essential for tailored treatment. The debulking followed by chemotherapy is the prevailing treatment, involving platinum-based drugs in combination with taxanes. However, the efficacy of chemotherapy is hindered by the development of chemoresistance, both acquired during treatment (acquired chemoresistance) and intrinsic to the patient (intrinsic chemoresistance). The emergence of chemoresistance leads to increased mortality rates, with many advanced patients experiencing disease relapse shortly after initial treatment. This review delves into the multifactorial nature of chemoresistance in OC, addressing mechanisms involving transport systems, apoptosis, DNA repair, and ovarian cancer stem cells (OCSCs). While previous research has identified genes associated with these mechanisms, the regulatory roles of non-coding RNA (ncRNA) and nuclear receptors in modulating gene expression to confer chemoresistance have remained poorly understood and underexplored. This comprehensive review aims to shed light on the genes linked to different chemoresistance mechanisms in OC and their intricate regulation by ncRNA and nuclear receptors. Specifically, we examine how these molecular players influence the chemoresistance mechanism. By exploring the interplay between these factors and gene expression regulation, this review seeks to provide a comprehensive mechanism driving chemoresistance in OC.

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“…CPI and CPIII are considered as Tier 1 and exploratory endogenous biomarkers for hepatic OATP1B1 and OATP1B3, respectively , because they are metabolically stable, and their basal level is not dependent on race or circadian rhythm . As a Tier 1 biomarker, CPI is recommended to be monitored in plasma in early-phase clinical studies, considering selectivity, sensitivity, and prediction performance.…”

Section: Introductionmentioning

confidence: 99%

An Isolated Perfused Rat Liver Model: Simultaneous LC-MS Quantification of Pitavastatin, Coproporphyrin I, and Coproporphyrin III Levels in the Rat Liver and Bile

Izat,

Kaplan,

Çelebier

et al. 2024

ACS Omega

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The isolated perfused rat liver (IPRL) model provides a mechanistic understanding of the organic-anion-transporting polypeptide (OATP/Oatp)-mediated pharmacokinetics in the preclinical evaluation, which often requires the use of control substrates (i.e., pitavastatin) and monitoring endogenous biomarkers (coproporphyrin I and III). This study aimed to develop and validate an LC-MS method allowing the simultaneous quantification of pitavastatin, coproporphyrin I (CPI), and coproporphyrin III (CPIII) in rat liver perfusion matrices (perfusate, liver homogenate, bile). The analysis was performed on a C18 column at 60 °C with 20 μL of sample injection. The mobile phases consisted of water with 0.1% formic acid and acetonitrile with 0.1% formic acid with a gradient flow of 0.5 mL/min. The assay was validated according to the ICH M10 Bioanalytical Method Validation Guideline (2022) for selectivity, calibration curve and range, matrix effect, carryover, accuracy, precision, and reinjection reproducibility. The method allowing the simultaneous quantification of pitavastatin, CPI, and CPIII was selective without having carryover and matrix effects. The linear calibration curves were obtained within various calibration ranges for three analytes in different matrices. Accuracy and precision values fulfilled the required limits. After 60 min perfusion with pitavastatin (1 μM), the cumulative amounts of pitavastatin in the liver and bile were 5.770 ± 1.504 and 0.852 ± 0.430 nmol/g liver, respectively. CPIII was a more dominant marker than CPI in both liver (0.028 ± 0.017 vs 0.013 ± 0.008 nmol/g liver) and bile (0.016 ± 0.011 vs 0.009 ± 0.007 nmol/g liver). The novel and validated bioanalytical method can be applied in further IPRL preparations investigating Oatp-mediated pharmacokinetics and DDIs.

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Membrane transporters in drug development and as determinants of precision medicine

Cited by 51 publications

References 241 publications

Structural basis of substrate transport and drug recognition by the human thiamine transporter SLC19A3

Structural basis of substrate transport and drug recognition by the human thiamine transporter SLC19A3

Novel players in the development of chemoresistance in ovarian cancer: ovarian cancer stem cells, non-coding RNA and nuclear receptors

An Isolated Perfused Rat Liver Model: Simultaneous LC-MS Quantification of Pitavastatin, Coproporphyrin I, and Coproporphyrin III Levels in the Rat Liver and Bile

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