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51. CONTRIBUTORS

Author

Allikmets, Rando, primary, Almashanu, Shlomo, additional, Ashcroft, Frances M., additional, Bates, Susan E., additional, Bauer, Bettina E., additional, Benabdelhak, Houssain, additional, Blight, Mark A., additional, Borst, Piet, additional, Callaghan, Richard, additional, Chambenoit, Olivier, additional, Chang, Geoffrey A., additional, Chen, Sixue, additional, Chimini, Giovanna, additional, Cole, Susan P.C., additional, Cui, Yunhai, additional, Dassa, Elie, additional, Dean, Michael, additional, Deeley, Roger G., additional, de Lima Pimenta, Andrea, additional, Fielding, Christopher, additional, Geisler, Markus, additional, Gentzsch, Martina, additional, Hanrahan, John W., additional, Higgins, Christopher F., additional, Holland, I. Barry, additional, Keppler, Dietrich, additional, Kerr, Ian D., additional, Kispal, Gyula, additional, Klein, Markus, additional, König, Jörg, additional, Konings, Wil N., additional, Kuchler, Karl, additional, Lankat-Buttgereit, Brigitte, additional, Légaré, Danielle, additional, Lill, Roland, additional, Linton, Kenneth J., additional, Martinoia, Enrico, additional, Matsuo, Michinori, additional, Nies, Anne T., additional, Elferink, Ronald Oude, additional, Ouellette, Marc, additional, Peng, Mingsheng, additional, Poelarends, Gerrit J., additional, Poolman, Bert, additional, Rea, Philip A., additional, Reid, Glen, additional, Riordan, John R., additional, Rosenberg, Mark F., additional, Roth, Christopher B., additional, Ruysschaert, Jean-Marie, additional, Ryder, Timothy, additional, Rzhetsky, Andrey, additional, Saeki, Tohru, additional, Sánchez-Fernández, Rocío, additional, Sarkadi, Balázs, additional, Schmitt, Lutz, additional, Schneider, Erwin, additional, Schüller, Christoph, additional, Sharom, Frances J., additional, Tampé, Robert, additional, Tusnády, Gábor E., additional, Ueda, Kazumitsu, additional, Valle, David, additional, van der Heide, Tiemen, additional, van Meer, Gerrit, additional, van Veen, Hendrik W., additional, Váradi, András, additional, Verschueren, Koen H.G., additional, Vigano, Catherine, additional, Wielinga, Peter, additional, Wilkinson, Anthony J., additional, Young, Joanne, additional, and Zelcer, Noam, additional

Published
2003
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60. Model system for the analysis of cell surface expression of human ABCA1

Author

Sarkadi Balázs, Váradi András, Andrikovics Hajnalka, Német Katalin, Szabó Katalin, Hegyi Zoltán, Kasza Ildikó, and Homolya László

Subjects
Cytology, QH573-671
Abstract

Abstract Background The ABCA1 protein plays a pivotal role in reverse cholesterol transport, by mediating the generation of HDL particles and removing cellular cholesterol. Both the proper expression of ABCA1 in the plasma membrane and the internalization along with apoA-I are required for function. Therefore, we developed a model system to investigate the effect of clinically relevant drugs on the cell surface appearance of ABCA1. Results By retroviral transduction system, we established stable mammalian cell lines expressing functional and non-functional ABCA1 variants, tagged with an extracellular hemagglutinin epitope. After characterization of the expression, proper localization and function of different ABCA1 variants, we followed quantitatively their cell surface expression by immunofluorescent staining, using flow cytometry. As expected, we found increased cell surface expression of ABCA1 after treatment with a calpain inhibitor, and observed a strong decrease in plasma membrane ABCA1 expression upon treatment with a trans-Golgi transport inhibitor, Brefeldin A. We tested cholesterol level lowering drugs and other potential inhibitors of ABCA1. Here we demonstrate that ezetimibe affects ABCA1 cell surface expression only in the case of a functional ABCA1. Conclusions Our model system allows a quantitative detection of cell surface expression of ABCA1, screening of substrates or specific inhibitors, and investigating transport regulation.

Published
2009
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61. In vitro transport of methotrexate by Drosophila Multidrug Resistance-associated Protein.

Author

Karasik, Agnes, Váradi, András, Szeri, Flóra, Karasik, Agnes, Váradi, András, and Szeri, Flóra

Abstract

Methotrexate (MTX) is a widely used chemotherapeutic agent, immune suppressant and antimalarial drug. It is a substrate of several human ABC proteins that confer multidrug resistance to cancer cells and determine compartmentalization of a wide range of physiological metabolites and endo or xenobiotics, by their primary active transport across biological membranes. The substrate specificity and tissue distribution of these promiscuous human ABC transporters show a high degree of redundancy, providing robustness to these key physiological and pharmacological processes, such as the elimination of toxins, e.g. methotrexate from the body. A similar network of proteins capable of transporting methotrexate has been recently suggested to exist in Drosophila melanogaster. One of the key players of this putative network is Drosophila Multidrug-resistance Associated Protein (DMRP). DMRP has been shown to be a highly active and promiscuous ABC transporter, capable of transporting various organic anions. Here we provide the first direct evidence that DMRP, expressed alone in a heterologous system lacking other, potentially functionally overlapping D. melanogaster organic anion transporters, is indeed able to transport methotrexate. Our in vitro results support the hypothesized but debated role of DMRP in in vivo methotrexate excretion.

Published
2018

62. The BiSearch web server

Author

Tusnády Gábor E, Simon István, Váradi András, and Arányi Tamás

Subjects
Computer applications to medicine. Medical informatics, R858-859.7, Biology (General), QH301-705.5
Abstract

Abstract Background A large number of PCR primer-design softwares are available online. However, only very few of them can be used for the design of primers to amplify bisulfite-treated DNA templates, necessary to determine genomic DNA methylation profiles. Indeed, the number of studies on bisulfite-treated templates exponentially increases as determining DNA methylation becomes more important in the diagnosis of cancers. Bisulfite-treated DNA is difficult to amplify since undesired PCR products are often amplified due to the increased sequence redundancy after the chemical conversion. In order to increase the efficiency of PCR primer-design, we have developed BiSearch web server, an online primer-design tool for both bisulfite-treated and native DNA templates. Results The web tool is composed of a primer-design and an electronic PCR (ePCR) algorithm. The completely reformulated ePCR module detects potential mispriming sites as well as undesired PCR products on both cDNA and native or bisulfite-treated genomic DNA libraries. Due to the new algorithm of the current version, the ePCR module became approximately hundred times faster than the previous one and gave the best performance when compared to other web based tools. This high-speed ePCR analysis made possible the development of the new option of high-throughput primer screening. BiSearch web server can be used for academic researchers at the http://bisearch.enzim.hu site. Conclusion BiSearch web server is a useful tool for primer-design for any DNA template and especially for bisulfite-treated genomes. The ePCR tool for fast detection of mispriming sites and alternative PCR products in cDNA libraries and native or bisulfite-treated genomes are the unique features of the new version of BiSearch software.

Published
2006
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63. Imaging Sigma-1 Receptor (S1R) Expression Using Iodine-124-Labeled 1-(4-Iodophenyl)-3-(2-adamantyl)guanidine ([124I]IPAG).

Author

Gangangari, Kishore K., Váradi, András, Majumdar, Susruta, Larson, Steven M., Pasternak, Gavril W., and Pillarsetty, NagaVara Kishore

Subjects
GUANIDINES, POSITRON emission tomography, BREAST cancer, IN vitro studies, CELL lines, IN vivo studies, BENZENE derivatives, RESEARCH, SIGMA-1 receptor, ANIMAL experimentation, RESEARCH methodology, ORGANIC compounds, EVALUATION research, IODINE radioisotopes, COMPARATIVE studies, GENE expression profiling, RADIOPHARMACEUTICALS, RESEARCH funding, BREAST tumors, MICE, EMISSION-computed tomography
Abstract

Purpose: Sigma-1 receptors (S1Rs) are overexpressed in almost all human cancers, especially in breast cancers. 1-(4-Iodophenyl)-3-(2-adamantyl)guanidine (IPAG) is a validated high-affinity S1R antagonist. The objective of the current study is to evaluate the potential of iodine-124-labeled IPAG ([124I]IPAG) to image S1R-overexpressing tumors.Procedures: [124I]IPAG was synthesized from a tributyltin precursor dissolved in ethanol using chloramine-T as oxidant. Purity was analyzed using HPLC. In vitro and in vivo studies were performed using the breast cancer cell line MCF-7. Competitive inhibition studies were performed using haloperidol and cold IPAG. Tumors were established in athymic nude mice by injecting 107 cells subcutaneously. Mice were imaged on micro-positron emission tomography (PET) at 4, 24, 48, 72, and 144 h post i.v. injection. Biodistribution studies were performed at same time points. In vivo tracer dilution studies were performed using excess of IPAG and haloperidol. The efficacy of [124I]IPAG to image tumors was evaluated in LNCaP tumor-bearing mice as well.Results: [124I]IPAG was synthesized in quantitative yield and in vitro studies indicated that [124I]IPAG binding was specific to S1R. PET imaging studies in MCF7 tumor-bearing mice reveal that [124I]IPAG accumulates in tumor and is preferentially retained while clearing from non-target organs. The tumor to background increases with time, and tumors could be clearly visualized starting from 24 h post administration. Similar results were obtained in mice bearing LNCaP tumors. In vivo tracer dilution studies showed that the uptake of [124I]IPAG could be competitively inhibited by excess of IPAG and haloperidol.Conclusions: [124I]IPAG was synthesized successfully in high yields, and in vitro and in vivo studies demonstrate specificity of [124I]IPAG. [124I]IPAG shows specific accumulation in tumors with increasing tumor to background ratio at later time points and therefore has high potential for imaging S1R-overexpressing cancers. [ABSTRACT FROM AUTHOR]

Published
2020
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68. New opioid receptor antagonist: Naltrexone-14- O -sulfate synthesis and pharmacology

Author

Zádor, Ferenc, primary, Király, Kornél, additional, Váradi, András, additional, Balogh, Mihály, additional, Fehér, Ágnes, additional, Kocsis, Dóra, additional, Erdei, Anna I., additional, Lackó, Erzsébet, additional, Zádori, Zoltán S., additional, Hosztafi, Sándor, additional, Noszál, Béla, additional, Riba, Pál, additional, Benyhe, Sándor, additional, Fürst, Susanna, additional, and Al-Khrasani, Mahmoud, additional

Published
2017
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69. Pyrophosphate Supplementation Prevents Chronic and Acute Calcification in ABCC6-Deficient Mice

Author

Pomozi, Viola, primary, Brampton, Christopher, additional, van de Wetering, Koen, additional, Zoll, Janna, additional, Calio, Bianca, additional, Pham, Kevin, additional, Owens, Jesse B., additional, Marh, Joel, additional, Moisyadi, Stefan, additional, Váradi, András, additional, Martin, Ludovic, additional, Bauer, Carolin, additional, Erdmann, Jeanette, additional, Aherrahrou, Zouhair, additional, and Le Saux, Olivier, additional

Published
2017
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72. Mitragynine/Corynantheidine Pseudoindoxyls As Opioid Analgesics with Mu Agonism and Delta Antagonism, Which Do Not Recruit β-Arrestin-2

Author

Váradi, András, primary, Marrone, Gina F., additional, Palmer, Travis C., additional, Narayan, Ankita, additional, Szabó, Márton R., additional, Le Rouzic, Valerie, additional, Grinnell, Steven G., additional, Subrath, Joan J., additional, Warner, Evelyn, additional, Kalra, Sanjay, additional, Hunkele, Amanda, additional, Pagirsky, Jeremy, additional, Eans, Shainnel O., additional, Medina, Jessica M., additional, Xu, Jin, additional, Pan, Ying-Xian, additional, Borics, Attila, additional, Pasternak, Gavril W., additional, McLaughlin, Jay P., additional, and Majumdar, Susruta, additional

Published
2016
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78. Synthesis of Carfentanil Amide Opioids Using the Ugi Multicomponent Reaction

Author

Váradi, András, primary, Palmer, Travis C., additional, Haselton, Nathan, additional, Afonin, Daniel, additional, Subrath, Joan J., additional, Le Rouzic, Valerie, additional, Hunkele, Amanda, additional, Pasternak, Gavril W., additional, Marrone, Gina F., additional, Borics, Attila, additional, and Majumdar, Susruta, additional

Published
2015
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80. ABCC6-mediated ATP secretion by the liver is the main source of the mineralization inhibitor inorganic pyrophosphate in the systemic circulation-brief report

Author

Jansen, Robert S, Duijst, Suzanne, Mahakena, Sunny, Sommer, Daniela, Szeri, Flóra, Váradi, András, Plomp, A.S., Bergen, Arthur A, Oude Elferink, Ronald P J, Borst, Piet, van de Wetering, Koen, Jansen, Robert S, Duijst, Suzanne, Mahakena, Sunny, Sommer, Daniela, Szeri, Flóra, Váradi, András, Plomp, A.S., Bergen, Arthur A, Oude Elferink, Ronald P J, Borst, Piet, and van de Wetering, Koen

Abstract

OBJECTIVE: Mutations in ABCC6 underlie the ectopic mineralization disorder pseudoxanthoma elasticum (PXE) and some forms of generalized arterial calcification of infancy, both of which affect the cardiovascular system. Using cultured cells, we recently showed that ATP-binding cassette subfamily C member 6 (ABCC6) mediates the cellular release of ATP, which is extracellularly rapidly converted into AMP and the mineralization inhibitor inorganic pyrophosphate (PPi). The current study was performed to determine which tissues release ATP in an ABCC6-dependent manner in vivo, where released ATP is converted into AMP and PPi, and whether human PXE ptients have low plasma PPi concentrations.APPROACH AND RESULTS: Using cultured primary hepatocytes and in vivo liver perfusion experiments, we found that ABCC6 mediates the direct, sinusoidal, release of ATP from the liver. Outside hepatocytes, but still within the liver vasculature, released ATP is converted into AMP and PPi. The absence of functional ABCC6 in patients with PXE leads to strongly reduced plasma PPi concentrations.CONCLUSIONS: Hepatic ABCC6-mediated ATP release is the main source of circulating PPi, revealing an unanticipated role of the liver in systemic PPi homeostasis. Patients with PXE have a strongly reduced plasma PPi level, explaining their mineralization disorder. Our results indicate that systemic PPi is relatively stable and that PXE, generalized arterial calcification of infancy, and other ectopic mineralization disorders could be treated with PPi supplementation therapy.

Published
2014

85. ABCC6–Mediated ATP Secretion by the Liver Is the Main Source of the Mineralization Inhibitor Inorganic Pyrophosphate in the Systemic Circulation—Brief Report

Author

Jansen, Robert S., primary, Duijst, Suzanne, additional, Mahakena, Sunny, additional, Sommer, Daniela, additional, Szeri, Flóra, additional, Váradi, András, additional, Plomp, Astrid, additional, Bergen, Arthur A., additional, Oude Elferink, Ronald P.J., additional, Borst, Piet, additional, and van de Wetering, Koen, additional

Published
2014
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90. Interaction with the 5D3 monoclonal antibody is regulated by intramolecular rearrangements but not by covalent dimer formation of the human ABCG2 multidrug transporter

Author

Özvegy-Laczka, Csilla, Laczkó, Rozália, Hegedűs, Csilla, Litman, Thomas, Várady, György, Goda, Katalin, Hegedűs, Tamás, Dokholyan, Nikolay V., Sorrentino, Brian P, Váradi, András, Sarkadi, Balázs, Özvegy-Laczka, Csilla, Laczkó, Rozália, Hegedűs, Csilla, Litman, Thomas, Várady, György, Goda, Katalin, Hegedűs, Tamás, Dokholyan, Nikolay V., Sorrentino, Brian P, Váradi, András, and Sarkadi, Balázs

Abstract

Human ABCG2 is a plasma membrane glycoprotein working as a homodimer or homo-oligomer. The protein plays an important role in the protection/detoxification of various tissues and may also be responsible for the multidrug-resistant phenotype of cancer cells. In our previous study we found that the 5D3 monoclonal antibody shows a function-dependent reactivity to an extracellular epitope of the ABCG2 transporter. In the current experiments we have further characterized the 5D3-ABCG2 interaction. The effect of chemical cross-linking and the modulation of extracellular S-S bridges on the transporter function and 5D3 reactivity of ABCG2 were investigated in depth. We found that several protein cross-linkers greatly increased 5D3 labeling in ABCG2 expressing HEK cells; however, there was no correlation between covalent dimer formation, the inhibition of transport activity, and the increase in 5D3 binding. Dithiothreitol treatment, which reduced the extracellular S-S bridge-forming cysteines of ABCG2, had no effect on transport function but caused a significant decrease in 5D3 binding. When analyzing ABCG2 mutants carrying Cys-to-Ala changes in the extracellular loop, we found that the mutant C603A (lacking the intermolecular S-S bond) showed comparable transport activity and 5D3 reactivity to the wild-type ABCG2. However, disruption of the intramolecular S-S bridge (in C592A, C608A, or C592A/C608A mutants) in this loop abolished 5D3 binding, whereas the function of the protein was preserved. Based on these results and ab initio folding simulations, we propose a model for the large extracellular loop of the ABCG2 protein.

Published
2008

91. ABCC6 Is a Basolateral Plasma Membrane Protein

Author

Pomozi, Viola, primary, Le Saux, Olivier, additional, Brampton, Christopher, additional, Apana, Ailea, additional, Iliás, Attila, additional, Szeri, Flóra, additional, Martin, Ludovic, additional, Monostory, Katalin, additional, Paku, Sándor, additional, Sarkadi, Balázs, additional, Szakács, Gergely, additional, and Váradi, András, additional

Published
2013
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94. Isocyanide-Based Multicomponent Reactions for the Synthesis of Heterocycles.

Author

Váradi, András, Palmer, Travis C., Dardashti, Rebecca Notis, and Majumdar, Susruta

Subjects
*ISOCYANIDES, *HETEROCYCLIC compounds, *NITRILIUM salts, *CHEMICAL synthesis, *DRUG design
Abstract

Multicomponent reactions (MCRs) are extremely popular owing to their facile execution, high atom-efficiency and the high diversity of products. MCRs can be used to access various heterocycles and highly functionalized scaffolds, and thus have been invaluable tools in total synthesis, drug discovery and bioconjugation. Traditional isocyanide-based MCRs utilize an external nucleophile attacking the reactive nitrilium ion, the key intermediate formed in the reaction of the imine and the isocyanide. However, when reactants with multiple nucleophilic groups (bisfunctional reactants) are used in the MCR, the nitrilium intermediate can be trapped by an intramolecular nucleophilic attack to form various heterocycles. The implications of nitrilium trapping along with widely applied conventional isocyanide-based MCRs in drug design are discussed in this review. [ABSTRACT FROM AUTHOR]

Published
2016
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