Search

Your search keyword '"Pöhner, Ina"' showing total 21 results
Start Over Author "Pöhner, Ina"
21 results on '"Pöhner, Ina"'

2. Design, synthesis and biological evaluation of antiparasitic dinitroaniline-ether phospholipid hybrids

Author

Roussaki, Marina, Magoulas, George E., Fotopoulou, Theano, Santarem, Nuno, Barrias, Emile, Pöhner, Ina, Luelmo, Sara, Afroudakis, Pantelis, Georgikopoulou, Kalliopi, Nevado, Paloma Tejera, Eick, Julia, Bifeld, Eugenia, Corral, María J., Jiménez-Antón, María Dolores, Ellinger, Bernhard, Kuzikov, Maria, Fragiadaki, Irini, Scoulica, Effie, Gul, Sheraz, Clos, Joachim, Prousis, Kyriakos C., Torrado, Juan J., Alunda, José María, Wade, Rebecca C., de Souza, Wanderley, Cordeiro da Silva, Anabela, and Calogeropoulou, Theodora

Published
2023
Full Text
View/download PDF

4. Accelerating Drug Discovery Efforts for Trypanosomatidic Infections Using an Integrated Transnational Academic Drug Discovery Platform

Author

Moraes, Carolina B., Witt, Gesa, Kuzikov, Maria, Ellinger, Bernhard, Calogeropoulou, Theodora, Prousis, Kyriakos C., Mangani, Stefano, Di Pisa, Flavio, Landi, Giacomo, Iacono, Lucia Dello, Pozzi, Cecilia, Freitas-Junior, Lucio H., dos Santos Pascoalino, Bruno, Bertolacini, Claudia P., Behrens, Birte, Keminer, Oliver, Leu, Jennifer, Wolf, Markus, Reinshagen, Jeanette, Cordeiro-da-Silva, Anabela, Santarem, Nuno, Venturelli, Alberto, Wrigley, Stephen, Karunakaran, Deepa, Kebede, Bethlehem, Pöhner, Ina, Müller, Wolfgang, Panecka-Hofman, Joanna, Wade, Rebecca C., Fenske, Martina, Clos, Joachim, Alunda, José María, Corral, María Jesús, Uliassi, Elisa, Bolognesi, Maria Laura, Linciano, Pasquale, Quotadamo, Antonio, Ferrari, Stefania, Santucci, Matteo, Borsari, Chiara, Costi, Maria Paola, and Gul, Sheraz

Published
2019
Full Text
View/download PDF

6. Hits and Lead Discovery in the Identification of New Drugs against the Trypanosomatidic Infections

Author

Calogeropoulou, Theodora, primary, Magoulas, George E., additional, Pöhner, Ina, additional, Panecka-Hofman, Joanna, additional, Linciano, Pasquale, additional, Ferrari, Stefania, additional, Santarem, Nuno, additional, Jiménez-Antón, Ma Dolores, additional, Olías-Molero, Ana Isabel, additional, Alunda, José María, additional, Silva, Anabela Cordeiro da, additional, Wade, Rebecca C., additional, and Costi, Maria Paola, additional

Published
2019
Full Text
View/download PDF

8. 11th German Conference on Chemoinformatics (GCC 2015): Fulda, Germany. 8–10 November 2015

Author

Fechner, Uli, de Graaf, Chris, Torda, Andrew E., Güssregen, Stefan, Evers, Andreas, Matter, Hans, Hessler, Gerhard, Richmond, Nicola J., Schmidtke, Peter, Segler, Marwin H. S., Waller, Mark P., Pleik, Stefanie, Shea, Joan-Emma, Levine, Zachary, Mullen, Ryan, van den Broek, Karina, Epple, Matthias, Kuhn, Hubert, Truszkowski, Andreas, Zielesny, Achim, Fraaije, Johannes (Hans), Gracia, Ruben Serral, Kast, Stefan M., Bulusu, Krishna C., Bender, Andreas, Yosipof, Abraham, Nahum, Oren, Senderowitz, Hanoch, Krotzky, Timo, Schulz, Robert, Wolber, Gerhard, Bietz, Stefan, Rarey, Matthias, Zimmermann, Markus O., Lange, Andreas, Ruff, Manuel, Heidrich, Johannes, Onlia, Ionut, Exner, Thomas E., Boeckler, Frank M., Bermudez, Marcel, Firaha, Dzmitry S., Hollóczki, Oldamur, Kirchner, Barbara, Tautermann, Christofer S., Volkamer, Andrea, Eid, Sameh, Turk, Samo, Rippmann, Friedrich, Fulle, Simone, Saleh, Noureldin, Saladino, Giorgio, Gervasio, Francesco L., Haensele, Elke, Banting, Lee, Whitley, David C., Oliveira Santos, Jana Sopkova-de, Bureau, Ronan, Clark, Timothy, Sandmann, Achim, Lanig, Harald, Kibies, Patrick, Heil, Jochen, Hoffgaard, Franziska, Frach, Roland, Engel, Julian, Smith, Steven, Basu, Debjit, Rauh, Daniel, Kohlbacher, Oliver, Boeckler, Frank M., Essex, Jonathan W., Bodnarchuk, Michael S., Ross, Gregory A., Finkelmann, Arndt R., Göller, Andreas H., Schneider, Gisbert, Husch, Tamara, Schütter, Christoph, Balducci, Andrea, Korth, Martin, Ntie-Kang, Fidele, Günther, Stefan, Sippl, Wolfgang, Mbaze, Luc Meva’a, Ntie-Kang, Fidele, Simoben, Conrad V., Lifongo, Lydia L., Ntie-Kang, Fidele, Judson, Philip, Barilla, Jiří, Lokajíček, Miloš V., Pisaková, Hana, Simr, Pavel, Kireeva, Natalia, Petrov, Alexandre, Ostroumov, Denis, Solovev, Vitaly P., Pervov, Vladislav S., Friedrich, Nils-Ole, Sommer, Kai, Rarey, Matthias, Kirchmair, Johannes, Proschak, Eugen, Weber, Julia, Moser, Daniel, Kalinowski, Lena, Achenbach, Janosch, Mackey, Mark, Cheeseright, Tim, Renner, Gerrit, Renner, Gerrit, Schmidt, Torsten C., Schram, Jürgen, Egelkraut-Holtus, Marion, van Oeyen, Albert, Kalliokoski, Tuomo, Fourches, Denis, Ibezim, Akachukwu, Mbah, Chika J., Adikwu, Umale M., Nwodo, Ngozi J., Steudle, Alexander, Masek, Brian B., Nagy, Stephan, Baker, David, Soltanshahi, Fred, Dorfman, Roman, Dubrucq, Karen, Patel, Hitesh, Koch, Oliver, Mrugalla, Florian, Kast, Stefan M., Ain, Qurrat U., Fuchs, Julian E., Owen, Robert M., Omoto, Kiyoyuki, Torella, Rubben, Pryde, David C., Glen, Robert, Bender, Andreas, Hošek, Petr, Spiwok, Vojtěch, Mervin, Lewis H., Barrett, Ian, Firth, Mike, Murray, David C., McWilliams, Lisa, Cao, Qing, Engkvist, Ola, Warszycki, Dawid, Śmieja, Marek, Bojarski, Andrzej J., Aniceto, Natalia, Freitas, Alex, Ghafourian, Taravat, Herrmann, Guido, Eigner-Pitto, Valentina, Naß, Alexandra, Kurczab, Rafał, Bojarski, Andrzej J., Lange, Andreas, Günther, Marcel B., Hennig, Susanne, Büttner, Felix M., Schall, Christoph, Sievers-Engler, Adrian, Ansideri, Francesco, Koch, Pierre, Stehle, Thilo, Laufer, Stefan, Böckler, Frank M., Zdrazil, Barbara, Montanari, Floriane, Ecker, Gerhard F., Grebner, Christoph, Hogner, Anders, Ulander, Johan, Edman, Karl, Guallar, Victor, Tyrchan, Christian, Ulander, Johan, Tyrchan, Christian, Klute, Wolfgang, Bergström, Fredrik, Kramer, Christian, Nguyen, Quoc Dat, Frach, Roland, Kibies, Patrick, Strohfeldt, Steven, Böttcher, Saraphina, Pongratz, Tim, Horinek, Dominik, Kast, Stefan M., Rupp, Bernd, Al-Yamori, Raed, Lisurek, Michael, Kühne, Ronald, Furtado, Filipe, van den Broek, Karina, Wessjohann, Ludger, Mathea, Miriam, Baumann, Knut, Mohamad-Zobir, Siti Zuraidah, Fu, Xianjun, Fan, Tai-Ping, Bender, Andreas, Kuhn, Maximilian A., Sotriffer, Christoph A., Zoufir, Azedine, Li, Xitong, Mervin, Lewis, Berg, Ellen, Polokoff, Mark, Ihlenfeldt, Wolf D., Ihlenfeldt, Wolf D., Pretzel, Jette, Alhalabi, Zayan, Fraczkiewicz, Robert, Waldman, Marvin, Clark, Robert D., Shaikh, Neem, Garg, Prabha, Kos, Alexander, Himmler, Hans-Jürgen, Sandmann, Achim, Jardin, Christophe, Sticht, Heinrich, Steinbrecher, Thomas B., Dahlgren, Markus, Cappel, Daniel, Lin, Teng, Wang, Lingle, Krilov, Goran, Abel, Robert, Friesner, Richard, Sherman, Woody, Pöhner, Ina A., Panecka, Joanna, Wade, Rebecca C., Bietz, Stefan, Schomburg, Karen T., Hilbig, Matthias, Rarey, Matthias, Jäger, Christian, Wieczorek, Vivien, Westerhoff, Lance M., Borbulevych, Oleg Y., Demuth, Hans-Ulrich, Buchholz, Mirko, Schmidt, Denis, Rickmeyer, Thomas, Krotzky, Timo, Kolb, Peter, Mittal, Sumit, Sánchez-García, Elsa, Nogueira, Mauro S., Oliveira, Tiago B., da Costa, Fernando B., and Schmidt, Thomas J.

Published
2016
Full Text
View/download PDF

9. Multitarget, Selective Compound Design Yields Potent Inhibitors of a Kinetoplastid Pteridine Reductase 1

Author

Pöhner, Ina, primary, Quotadamo, Antonio, additional, Panecka-Hofman, Joanna, additional, Luciani, Rosaria, additional, Santucci, Matteo, additional, Linciano, Pasquale, additional, Landi, Giacomo, additional, Di Pisa, Flavio, additional, Dello Iacono, Lucia, additional, Pozzi, Cecilia, additional, Mangani, Stefano, additional, Gul, Sheraz, additional, Witt, Gesa, additional, Ellinger, Bernhard, additional, Kuzikov, Maria, additional, Santarem, Nuno, additional, Cordeiro-da-Silva, Anabela, additional, Costi, Maria P., additional, Venturelli, Alberto, additional, and Wade, Rebecca C., additional

Published
2022
Full Text
View/download PDF

10. SARS‐CoV‐2–host proteome interactions for antiviral drug discovery

Author

Liu, Xiaonan, primary, Huuskonen, Sini, additional, Laitinen, Tuomo, additional, Redchuk, Taras, additional, Bogacheva, Mariia, additional, Salokas, Kari, additional, Pöhner, Ina, additional, Öhman, Tiina, additional, Tonduru, Arun Kumar, additional, Hassinen, Antti, additional, Gawriyski, Lisa, additional, Keskitalo, Salla, additional, Vartiainen, Maria K, additional, Pietiäinen, Vilja, additional, Poso, Antti, additional, and Varjosalo, Markku, additional

Published
2021
Full Text
View/download PDF

11. MatchTope: A tool to predict the cross reactivity of peptides complexed with Major Histocompatibility Complex I.

Author

de Almeida Mendes, Marcus Fabiano, de Souza Bragatte, Marcelo, Vianna, Priscila, de Freitas, Martiela Vaz, Pöhner, Ina, Richter, Stefan, Wade, Rebecca C., Mauro Salzano, Francisco, and Fioravanti Vieira, Gustavo

Subjects
MAJOR histocompatibility complex, PEPTIDES, AMINO acid sequence, IMMUNE response, IMMUNE system, HISTOCOMPATIBILITY class I antigens
Abstract

The therapeutic targeting of the immune system, for example in vaccinology and cancer treatment, is a challenging task and the subject of active research. Several in silico tools used for predicting immunogenicity are based on the analysis of peptide sequences binding to the Major Histocompatibility Complex (pMHC). However, few of these bioinformatics tools take into account the pMHC threedimensional structure. Here, we describe a new bioinformatics tool, MatchTope, developed for predicting peptide similarity, which can trigger cross-reactivity events, by computing and analyzing the electrostatic potentials of pMHC complexes. We validated MatchTope by using previously published data from in vitro assays. We thereby demonstrate the strength of MatchTope for similarity prediction between targets derived from several pathogens as well as for indicating possible cross responses between self and tumor peptides. Our results suggest that MatchTope can enhance and speed up future studies in the fields of vaccinology and cancer immunotherapy. [ABSTRACT FROM AUTHOR]

Published
2022
Full Text
View/download PDF

12. Computational approaches to drug design against the folate & biopterin pathways of parasites causing neglected tropical diseases

Author

Pöhner, Ina

Subjects
parasitic diseases, 500 Natural sciences and mathematics
Abstract

The neglected tropical diseases leishmaniasis, Chagas disease and African trypanosomiasis, are inflicted by different trypanosomatid parasites and continue to spread. The limited number of available treatment options suffer from side effects and resistance issues, creating a need for novel anti-parasitic medicines. A target pathway of interest for developing anti-trypanosomatidic agents is the folate and biopterin metabolism. Trypanosomatids are auxotrophs for these metabolites and depend on their reductive activation by dihydrofolate reductase (DHFR) and pteridine reductase 1 (PTR1). However, inhibition of the anti-cancer and anti-bacterial target DHFR failed in trypanosomatids, since PTR1 provides a metabolic bypass of the DHFR activity. Thus, targeting of more than a single protein is required to interfere with the trypanosomatidic folate and biopterin pathway function. PTR1 is unique to the parasites, whereas DHFR has a human homolog representing an important off-target for compound development. Comparative studies of the sequences, structural data and physicochemical properties of the binding pockets were carried out for PTR1 and DHFR. The computational mapping revealed similarities between the different trypanosomatidic targets and important differences to human off-targets, which were translated into guidelines for the optimization of specific inhibitors of the parasitic target enzymes. Comparative modeling of ten further Leishmania major folate and biopterin pathway proteins expanded the comparison to a near-complete folate pathway pocketome and three biopterin-binding enzyme pockets. From this analysis, further potential off-targets for PTR1-specific inhibitors and additional side targets, for example the methylene tetrahydrofolate reductase or the folylpolyglutamate synthase, were suggested. Structure-based design and optimization were then carried out based on the target mapping. Building on previously developed thiadiazole-based Leishmania major PTR1 inhibitors, computational docking supported the determination of a structure-activity relationship (SAR) and the design of more effective thiadiazole-based and benzothiazole-based Trypanosoma brucei PTR1 inhibitors. Docking approaches further revealed the SAR for flavonoid inhibitors of different PTR1 variants and allowed for the proposal of core-hopping strategies. Novel pteridine-based inhibitors permitted the combined selective targeting of PTR1, with picomolar binding affinity, and parasite DHFR. Their design and SAR evaluation was informed by the computational docking predictions and additional efforts to improve the in vitro on-parasite effect on the basis of computationally predicted physicochemical compound descriptors supported the development of compounds with low micromolar in vitro activity against T. brucei bloodstream forms. Computational docking-derived SARs and their use in the design of improved inhibitors were thus successfully coupled with comparative mapping of protein binding pockets and computation-based optimization routines beyond the target level. This computational framework is applicable to the future development of anti-trypanosomatidic agents with different chemical scaffolds.

Published
2020

13. The trypanocidal benzoxaborole AN7973 inhibits trypanosome mRNA processing

Author

Begolo, Daniela, Vincent, Isabel M., Giordani, Federica, Pöhner, Ina, Witty, Michael J., Rowan, Timothy G., Bengaly, Zakaria, Gillingwater, Kirsten, Freund, Yvonne, Wade, Rebecca C., Barrett, Michael P., and Clayton, Christine

Subjects
QH301-705.5, Immunologic diseases. Allergy, RC581-607, Biology (General)
Abstract

Kinetoplastid parasites—trypanosomes and leishmanias—infect millions of humans and cause economically devastating diseases of livestock, and the few existing drugs have serious deficiencies. Benzoxaborole-based compounds are very promising potential novel anti-trypanosomal therapies, with candidates already in human and animal clinical trials. We investigated the mechanism of action of several benzoxaboroles, including AN7973, an early candidate for veterinary trypanosomosis. In all kinetoplastids, transcription is polycistronic. Individual mRNA 5'-ends are created by trans splicing of a short leader sequence, with coupled polyadenylation of the preceding mRNA. Treatment of Trypanosoma brucei with AN7973 inhibited trans splicing within 1h, as judged by loss of the Y-structure splicing intermediate, reduced levels of mRNA, and accumulation of peri-nuclear granules. Methylation of the spliced leader precursor RNA was not affected, but more prolonged AN7973 treatment caused an increase in S-adenosyl methionine and methylated lysine. Together, the results indicate that mRNA processing is a primary target of AN7973. Polyadenylation is required for kinetoplastid trans splicing, and the EC50 for AN7973 in T. brucei was increased three-fold by over-expression of the T. brucei cleavage and polyadenylation factor CPSF3, identifying CPSF3 as a potential molecular target. Molecular modeling results suggested that inhibition of CPSF3 by AN7973 is feasible. Our results thus chemically validate mRNA processing as a viable drug target in trypanosomes. Several other benzoxaboroles showed metabolomic and splicing effects that were similar to those of AN7973, identifying splicing inhibition as a common mode of action and suggesting that it might be linked to subsequent changes in methylated metabolites. Granule formation, splicing inhibition and resistance after CPSF3 expression did not, however, always correlate and prolonged selection of trypanosomes in AN7973 resulted in only 1.5-fold resistance. It is therefore possible that the modes of action of oxaboroles that target trypanosome mRNA processing might extend beyond CPSF3 inhibition.

Published
2018

14. Enhancement of Benzothiazoles as Pteridine Reductase-1 Inhibitors for the Treatment of Trypanosomatidic Infections

Author

Linciano, Pasquale, primary, Pozzi, Cecilia, additional, Iacono, Lucia dello, additional, di Pisa, Flavio, additional, Landi, Giacomo, additional, Bonucci, Alessio, additional, Gul, Sheraz, additional, Kuzikov, Maria, additional, Ellinger, Bernhard, additional, Witt, Gesa, additional, Santarem, Nuno, additional, Baptista, Catarina, additional, Franco, Caio, additional, Moraes, Carolina B., additional, Müller, Wolfgang, additional, Wittig, Ulrike, additional, Luciani, Rosaria, additional, Sesenna, Antony, additional, Quotadamo, Antonio, additional, Ferrari, Stefania, additional, Pöhner, Ina, additional, Cordeiro-da-Silva, Anabela, additional, Mangani, Stefano, additional, Costantino, Luca, additional, and Costi, Maria Paola, additional

Published
2019
Full Text
View/download PDF

15. Comparative mapping of on-targets and off-targets for the discovery of anti-trypanosomatid folate pathway inhibitors

Author

Panecka-Hofman, Joanna, primary, Pöhner, Ina, additional, Spyrakis, Francesca, additional, Zeppelin, Talia, additional, Di Pisa, Flavio, additional, Dello Iacono, Lucia, additional, Bonucci, Alessio, additional, Quotadamo, Antonio, additional, Venturelli, Alberto, additional, Mangani, Stefano, additional, Costi, Maria Paola, additional, and Wade, Rebecca C., additional

Published
2017
Full Text
View/download PDF

16. Exploiting the 2-Amino-1,3,4-thiadiazole Scaffold To Inhibit Trypanosoma brucei Pteridine Reductase in Support of Early-Stage Drug Discovery

Author

Linciano, Pasquale, primary, Dawson, Alice, additional, Pöhner, Ina, additional, Costa, David M., additional, Sá, Monica S., additional, Cordeiro-da-Silva, Anabela, additional, Luciani, Rosaria, additional, Gul, Sheraz, additional, Witt, Gesa, additional, Ellinger, Bernhard, additional, Kuzikov, Maria, additional, Gribbon, Philip, additional, Reinshagen, Jeanette, additional, Wolf, Markus, additional, Behrens, Birte, additional, Hannaert, Véronique, additional, Michels, Paul A. M., additional, Nerini, Erika, additional, Pozzi, Cecilia, additional, di Pisa, Flavio, additional, Landi, Giacomo, additional, Santarem, Nuno, additional, Ferrari, Stefania, additional, Saxena, Puneet, additional, Lazzari, Sandra, additional, Cannazza, Giuseppe, additional, Freitas-Junior, Lucio H., additional, Moraes, Carolina B., additional, Pascoalino, Bruno S., additional, Alcântara, Laura M., additional, Bertolacini, Claudia P., additional, Fontana, Vanessa, additional, Wittig, Ulrike, additional, Müller, Wolfgang, additional, Wade, Rebecca C., additional, Hunter, William N., additional, Mangani, Stefano, additional, Costantino, Luca, additional, and Costi, Maria P., additional

Published
2017
Full Text
View/download PDF

17. Chroman-4-One Derivatives Targeting Pteridine Reductase 1 and Showing Anti-Parasitic Activity

Author

Di Pisa, Flavio, primary, Landi, Giacomo, additional, Dello Iacono, Lucia, additional, Pozzi, Cecilia, additional, Borsari, Chiara, additional, Ferrari, Stefania, additional, Santucci, Matteo, additional, Santarem, Nuno, additional, Cordeiro-da-Silva, Anabela, additional, Moraes, Carolina, additional, Alcantara, Laura, additional, Fontana, Vanessa, additional, Freitas-Junior, Lucio, additional, Gul, Sheraz, additional, Kuzikov, Maria, additional, Behrens, Birte, additional, Pöhner, Ina, additional, Wade, Rebecca, additional, Costi, Maria, additional, and Mangani, Stefano, additional

Published
2017
Full Text
View/download PDF

19. 11th German Conference on Chemoinformatics (GCC 2015)

Author

Fechner, Uli, de Graaf, Chris, Torda, Andrew E., Güssregen, Stefan, Evers, Andreas, Matter, Hans, Hessler, Gerhard, Richmond, Nicola J., Schmidtke, Peter, Segler, Marwin H. S., Waller, Mark P., Pleik, Stefanie, Shea, Joan-Emma, Levine, Zachary, Mullen, Ryan, van den Broek, Karina, Epple, Matthias, Kuhn, Hubert, Truszkowski, Andreas, Zielesny, Achim, Fraaije, Johannes, Gracia, Ruben Serral, Kast, Stefan M., Bulusu, Krishna C., Bender, Andreas, Yosipof, Abraham, Nahum, Oren, Senderowitz, Hanoch, Krotzky, Timo, Schulz, Robert, Wolber, Gerhard, Bietz, Stefan, Rarey, Matthias, Zimmermann, Markus O., Lange, Andreas, Ruff, Manuel, Heidrich, Johannes, Onlia, Ionut, Exner, Thomas E., Boeckler, Frank M., Bermudez, Marcel, Firaha, Dzmitry S., Hollóczki, Oldamur, Kirchner, Barbara, Tautermann, Christofer S., Volkamer, Andrea, Eid, Sameh, Turk, Samo, Rippmann, Friedrich, Fulle, Simone, Saleh, Noureldin, Saladino, Giorgio, Gervasio, Francesco L., Haensele, Elke, Banting, Lee, Whitley, David C., Oliveira Santos, Jana Sopkova-de, Bureau, Ronan, Clark, Timothy, Sandmann, Achim, Lanig, Harald, Kibies, Patrick, Heil, Jochen, Hoffgaard, Franziska, Frach, Roland, Engel, Julian, Smith, Steven, Basu, Debjit, Rauh, Daniel, Kohlbacher, Oliver, Essex, Jonathan W., Bodnarchuk, Michael S., Ross, Gregory A., Finkelmann, Arndt R., Göller, Andreas H., Schneider, Gisbert, Husch, Tamara, Schütter, Christoph, Balducci, Andrea, Korth, Martin, Ntie-Kang, Fidele, Günther, Stefan, Sippl, Wolfgang, Mbaze, Luc Meva’a, Simoben, Conrad V., Lifongo, Lydia L., Judson, Philip, Barilla, Jiří, Lokajíček, Miloš V., Pisaková, Hana, Simr, Pavel, Kireeva, Natalia, Petrov, Alexandre, Ostroumov, Denis, Solovev, Vitaly P., Pervov, Vladislav S., Friedrich, Nils-Ole, Sommer, Kai, Kirchmair, Johannes, Proschak, Eugen, Weber, Julia, Moser, Daniel, Kalinowski, Lena, Achenbach, Janosch, Mackey, Mark, Cheeseright, Tim, Renner, Gerrit, Schmidt, Torsten C., Schram, Jürgen, Egelkraut-Holtus, Marion, van Oeyen, Albert, Kalliokoski, Tuomo, Fourches, Denis, Ibezim, Akachukwu, Mbah, Chika J., Adikwu, Umale M., Nwodo, Ngozi J., Steudle, Alexander, Masek, Brian B., Nagy, Stephan, Baker, David, Soltanshahi, Fred, Dorfman, Roman, Dubrucq, Karen, Patel, Hitesh, Koch, Oliver, Mrugalla, Florian, Ain, Qurrat U., Fuchs, Julian E., Owen, Robert M., Omoto, Kiyoyuki, Torella, Rubben, Pryde, David C., Glen, Robert, Hošek, Petr, Spiwok, Vojtěch, Mervin, Lewis H., Barrett, Ian, Firth, Mike, Murray, David C., McWilliams, Lisa, Cao, Qing, Engkvist, Ola, Warszycki, Dawid, Śmieja, Marek, Bojarski, Andrzej J., Aniceto, Natalia, Freitas, Alex, Ghafourian, Taravat, Herrmann, Guido, Eigner-Pitto, Valentina, Naß, Alexandra, Kurczab, Rafał, Günther, Marcel B., Hennig, Susanne, Büttner, Felix M., Schall, Christoph, Sievers-Engler, Adrian, Ansideri, Francesco, Koch, Pierre, Stehle, Thilo, Laufer, Stefan, Böckler, Frank M., Zdrazil, Barbara, Montanari, Floriane, Ecker, Gerhard F., Grebner, Christoph, Hogner, Anders, Ulander, Johan, Edman, Karl, Guallar, Victor, Tyrchan, Christian, Klute, Wolfgang, Bergström, Fredrik, Kramer, Christian, Nguyen, Quoc Dat, Strohfeldt, Steven, Böttcher, Saraphina, Pongratz, Tim, Horinek, Dominik, Rupp, Bernd, Al-Yamori, Raed, Lisurek, Michael, Kühne, Ronald, Furtado, Filipe, Wessjohann, Ludger, Mathea, Miriam, Baumann, Knut, Mohamad-Zobir, Siti Zuraidah, Fu, Xianjun, Fan, Tai-Ping, Kuhn, Maximilian A., Sotriffer, Christoph A., Zoufir, Azedine, Li, Xitong, Mervin, Lewis, Berg, Ellen, Polokoff, Mark, Ihlenfeldt, Wolf D., Pretzel, Jette, Alhalabi, Zayan, Fraczkiewicz, Robert, Waldman, Marvin, Clark, Robert D., Shaikh, Neem, Garg, Prabha, Kos, Alexander, Himmler, Hans-Jürgen, Jardin, Christophe, Sticht, Heinrich, Steinbrecher, Thomas B., Dahlgren, Markus, Cappel, Daniel, Lin, Teng, Wang, Lingle, Krilov, Goran, Abel, Robert, Friesner, Richard, Sherman, Woody, Pöhner, Ina A., Panecka, Joanna, Wade, Rebecca C., Schomburg, Karen T., Hilbig, Matthias, Jäger, Christian, Wieczorek, Vivien, Westerhoff, Lance M., Borbulevych, Oleg Y., Demuth, Hans-Ulrich, Buchholz, Mirko, Schmidt, Denis, Rickmeyer, Thomas, Kolb, Peter, Mittal, Sumit, Sánchez-García, Elsa, Nogueira, Mauro S., Oliveira, Tiago B., da Costa, Fernando B., and Schmidt, Thomas J.

Subjects
Physical and Theoretical Chemistry, Library and Information Sciences, Computer Graphics and Computer-Aided Design, Computer Science Applications
Full Text
View/download PDF

21. The trypanocidal benzoxaborole AN7973 inhibits trypanosome mRNA processing.

Author

Begolo D, Vincent IM, Giordani F, Pöhner I, Witty MJ, Rowan TG, Bengaly Z, Gillingwater K, Freund Y, Wade RC, Barrett MP, and Clayton C

Subjects
Animals, Benzoxazoles chemistry, Cattle, Drug Resistance genetics, Goats, Humans, Mice, Protozoan Proteins genetics, Protozoan Proteins metabolism, RNA Processing, Post-Transcriptional drug effects, RNA, Messenger genetics, RNA, Messenger metabolism, RNA, Protozoan genetics, Trans-Splicing drug effects, Trypanocidal Agents chemistry, Trypanosoma brucei brucei genetics, Trypanosoma congolense drug effects, Trypanosoma congolense genetics, Trypanosoma congolense metabolism, Trypanosoma vivax drug effects, Trypanosoma vivax genetics, Trypanosoma vivax metabolism, Trypanosomiasis drug therapy, Trypanosomiasis parasitology, Benzoxazoles pharmacology, RNA, Protozoan metabolism, Trypanocidal Agents pharmacology, Trypanosoma brucei brucei drug effects, Trypanosoma brucei brucei metabolism
Abstract

Kinetoplastid parasites-trypanosomes and leishmanias-infect millions of humans and cause economically devastating diseases of livestock, and the few existing drugs have serious deficiencies. Benzoxaborole-based compounds are very promising potential novel anti-trypanosomal therapies, with candidates already in human and animal clinical trials. We investigated the mechanism of action of several benzoxaboroles, including AN7973, an early candidate for veterinary trypanosomosis. In all kinetoplastids, transcription is polycistronic. Individual mRNA 5'-ends are created by trans splicing of a short leader sequence, with coupled polyadenylation of the preceding mRNA. Treatment of Trypanosoma brucei with AN7973 inhibited trans splicing within 1h, as judged by loss of the Y-structure splicing intermediate, reduced levels of mRNA, and accumulation of peri-nuclear granules. Methylation of the spliced leader precursor RNA was not affected, but more prolonged AN7973 treatment caused an increase in S-adenosyl methionine and methylated lysine. Together, the results indicate that mRNA processing is a primary target of AN7973. Polyadenylation is required for kinetoplastid trans splicing, and the EC50 for AN7973 in T. brucei was increased three-fold by over-expression of the T. brucei cleavage and polyadenylation factor CPSF3, identifying CPSF3 as a potential molecular target. Molecular modeling results suggested that inhibition of CPSF3 by AN7973 is feasible. Our results thus chemically validate mRNA processing as a viable drug target in trypanosomes. Several other benzoxaboroles showed metabolomic and splicing effects that were similar to those of AN7973, identifying splicing inhibition as a common mode of action and suggesting that it might be linked to subsequent changes in methylated metabolites. Granule formation, splicing inhibition and resistance after CPSF3 expression did not, however, always correlate and prolonged selection of trypanosomes in AN7973 resulted in only 1.5-fold resistance. It is therefore possible that the modes of action of oxaboroles that target trypanosome mRNA processing might extend beyond CPSF3 inhibition., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: Yvonne Freund was employed by Anacor Pharmaceuticals. Benzoxaboroles were supplied by Anacor Pharmaceuticals (YF) which was later taken over by Pfizer. This does not alter our adherence to all the PLOS Pathogens policies on sharing data and materials.

Published
2018
Full Text
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results