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Luise Krauth-Siegel 
Trypanosomes & Drug Design

Groupleader: Luise Krauth-Siegel

Ebersoll, S., Musunda, B., Schmenger, T., Dirdjaja, N., Bonilla, M., Manta, B., Ulrich, K., Comini, M. A., and Krauth-Siegel, R. L. (2018) A glutaredoxin in the mitochondrial intermembrane space has stage-specific functions in the thermo-tolerance and proliferation of African trypanosomes.
Redox Biology 15, 532-547.
De Gasparo, R., Persch, E., Bryson, S. Hentzen, N., Kaiser, M., Pai, E. F., Krauth-Siegel, R. L., and Diederich, F. (2018) Biological evaluation and X-ray co-crystal structures of cyclohexylpyrrolidine ligands for trypanothione reductase (TR), an enzyme from the redox metabolism of Trypanosoma.
Chem. Med. Chem. 13, 957-967.

Jagu, E., Pomel, S., Díez-Martínez, A., Ramiandrasoa, F., Krauth-Siegel, R. L., Pethe, S., Blonski, C., Labruère, R. and Loiseau, P. M. (2017) Synthesis and in vitro antikinetoplastid activity of polyamine-hydroxybenzotriazole conjugates,
Bioorg. Med. Chem. 25, 84-90.
Schirmeister, T., Schmitz, J., Jung, S., Schmenger, T., Krauth-Siegel, R. L. and Gütschow, M. (2017) Evaluation of dipeptide nitriles as inhibitors of rhodesain, a major cysteine protease of Trypanosoma brucei.
Bioorg. Med. Chem. Lett. 27, 45-50.
Chacón-Vargas, K. F., Nogueda-Torres, B.; Sánchez-Torres, L. E., Suarez-Contreras, E., Villalobos-Rocha, J. C., Torres-Martinez, Y., Lara-Ramirez, E. E., Fiorani, G., Krauth-Siegel, R. L., Bolognesi, M. L., Monge, A., Rivera, G. (2017) Trypanocidal activity of quinoxaline 1,4 di-N-oxide derivatives as trypanothione reductase inhibitors,
Molecules 22, 220
Ulrich, K., Finkenzeller, C., Merker, S., Rojas, F., Matthews, K., Ruppert, T. and Krauth-Siegel, R. L. (2017) Stress-induced protein S-glutathionylation and S-trypanothiolation in African trypanosomes – a quantitative redox proteome and thiol analysis.
 Antiox. Redox Sign. 27, 517-533.
Wagner, A., Diehl, E., Krauth-Siegel, R. L. and Hellmich, U. A. (2017) Backbone NMR assignments of tryparedoxin, the central protein in the hydroperoxide detoxification cascade of African trypanosomes, in the oxidized and reduced form.
Biomol NMR Assign. 11, 193-196.
Schmidt, I., Göllner, S., Fuß, A., Stich, A., Kucharski, A., Schirmeister, T.,   Katzowitsch, E., Bruhn, H., Miliu, A., Krauth-Siegel, R. L., Holzgrabe, U. (2017) Bistacrines as potential antitrypanosomal agents,
Bioorg. Med. Chem. 25, 4526-4531.
Previti, S., Ettari, R., Cosconati, S., Amendola, G., Chouchene, K., Wagner, A., Hellmich, U. A., Ulrich, K., Krauth-Siegel, R. L., Wich, P. R., Schmid, I., Schirmeister, T., Gut, J., Rosenthal, P. J., Grasso, S. and Zapalà, M. (2017) Development of novel peptide-based Michael acceptors targeting rhodesain and falcipain-2 for the treatment of neglected tropical diseases (NTDs)
J. Med. Chem. 60, 6911-6923.
Uliassi, E. Fiorani, G., Krauth-Siegel, R. L., Bergamini, C., Fato, R., Bianchini,    G., Menéndez, J. C., Molina, M. T., López-Montero, E., Falchi, F., Cavalli, A., Gul, S., Kuzikov, M., Ellinger, B., Moraes, C. B., Freitas-Junior, L. H., Borsari, C., Costi, M. P. and Bolognesi, M. L. (2017) Crassiflorone derivatives that inhibit Trypanosoma brucei glyceraldehyde-3-phosphate dehydrogenase (TbGAPDH) and Trypanosoma cruzi trypanothione reductase (TcTR) and display activity against Trypanosoma brucei parasites.
Eur. J. Med. Chem. 141, 138-148.

Schaffroth, C., Bogacz, M., Dirdjaja, N., Nissen, A. and Krauth-Siegel, R. L. (2016) The cytosolic or the mitochondrial glutathione peroxidase-type tryparedoxin peroxidase is sufficient to protect procyclic Trypanosoma brucei from iron-mediated mitochondrial damage and lysis.
Mol. Microbiol. 99, 172-187.
Marcu, A., Schurigt, U., Müller, K., Moll, H., Krauth-Siegel, R. L. and Prinz, H. (2016) Inhibitory effect of phenothiazine- and phenoxazine-derived chloroacetamides on Leishmania major growth and Trypanosoma brucei trypanothione reductase.
Eur. J. Med. Chem. 108, 436-443.
Leroux, A. and Krauth-Siegel, R. L. (2016) Thiol redox biology of trypanosomatids and potential targets for chemotherapy.
Mol. Biochem. Parasitol. 206, 67-74.
Olmo, F., Cussó, O., Marín, C., Rosales, M. J., Urbonová, K., Krauth-Siegel, R. L., Costas, M., Ribas, X. and Sánchez-Moreno, M. (2016) In vitro and in vivo identification of tetradentated polyamine complexes as highly efficient metallodrugs against Trypanosoma cruzi.
Exp. Parasitol. 164, 20-30.
Liu, I., Bogacz, M., Schaffroth, C., Dirdjaja, N., and Krauth-Siegel, R. L. (2016) Catalytic properties, localization, and in vivo role of Px IV, a novel tryparedoxin peroxidase of Trypanosoma brucei.
Mol. Biochem. Parasitol. 207, 84-88.
Latorre, A., Schirmeister, T., Kesselring, J., Jung, S., Johé, P., Hellmich, U. A., Heilos, A., Engels, B., Krauth-Siegel, R. L., Dirdjaja, N., Bou-Iserte, L., Rodríguez, S. and González, F. V. (2016) Dipeptidyl nitroalkenes as potent reversible inhibitors of cysteine proteases rhodesain and cruzain.
ACS Medic. Chem. Letters 7, 1073-1076.

Beig, M., Oellien, F., Garoff, L., Noack, S., Krauth-Siegel, R. L. and Selzer, P. M. (2015) Trypanothione reductase: A target protein for a combined in vitro and in silico screening approach.
PLoS Negl. Trop. Dis. 9(6): e0003773.
Rahbari, M., Diederich, K., Becker, K., Krauth-Siegel, R. L. and Jortzik, E. (2015) Detection of thiol-based switch processes in parasites – facts and future. Biol. Chem. 396, 445-463.
Musunda, B., Benítez, D., Dirdjaja, N., Comini, M. A. and Krauth-Siegel, R. L. (2015) Glutaredoxin-deficiency confers bloodstream Trypanosoma brucei with improved thermotolerance.
Mol. Biochem. Parasitol. 204, 93-105.

Belluti, F., Uliassi, E., Veronesi, G., Bergamini, C., Kaiser, M., Brun, R., Viola, A., Fato, R., Michels, P. A. M., Krauth-Siegel, R. L., Cavalli, A. and Bolognesi, M. L. (2014) Toward the development of dual-targeted glyceraldehyde-3-phosphate dehydrogenase/trypanothione reductase inhibitors against Trypanosoma brucei and Trypanosoma cruzi.
Chem. Med. Chem. 9, 371-382.
Hiller, C., Nissen, A., Benítez, D., Comini, M. A. and Krauth-Siegel, R. L. (2014) Cytosolic peroxidases protect the lysosome of bloodstream African trypanosomes from iron-mediated membrane damage.
PLoS Pathogens e1004075.
Persch, E., Bryson, S., Todoroff, N. K., Eberle, C., Thelemann, J., Dirdjaja, N., Kaiser, M., Weber, M., Derbani, H., Brun, R., Schneider, G., Pai, E. F., Krauth-Siegel, R. L. and Diederich, F. (2014) Binding to large enzyme pockets: Small-molecule inhibitors of trypanothione reductase.
Chem. Med. Chem. 9, 1880-1891.
Comini, M. A., Krauth-Siegel, R. L. and Bellanda, M. (2013) Mono- and dithiol glutaredoxins in the trypanothione-based redox metabolism of pathogenic trypanosomes.
Antiox. Redox Sign. 19, 708-722.
Manta, B., Pavan, C., Sturlese, M., Medeiros, A., Crispo, M., Berndt, C., Krauth-Siegel, R. L., Bellanda, M. and Comini, M. A. (2013) Iron-sulfur cluster (ISC) binding by mitochondrial monothiol glutaredoxin-1 of Trypanosoma brucei: molecular basis of ISC coordination and relevance for parasite infectivity.
Antiox. Redox Sign. 19, 665-682.
Leroux, A.L., Haanstra, J. R., Bakker, B. M. and Krauth-Siegel, R. L. (2013) Dissecting the catalytic mechanism of Trypanosoma brucei trypanothione synthetase by kinetic analysis and computational modelling.
J. Biol. Chem. 288, 23751-23764.

Lizzi F, Veronesi G, Belluti F, Bergamini C, López-Sánchez A, Kaiser M, Brun R, Krauth-Siegel RL, Hall DG, Rivas L, Bolognesi ML. Conjugation of quinones with natural polyamines: toward an expanded antitrypanosomatid profile.
J Med Chem. 2012; 55(23):10490-500.

Eichhorn T, Schloissnig S, Hahn B, Wendler A, Mertens R, Lehmann WD, Krauth-Siegel RL, Efferth T. Bioinformatic and experimental fishing for artemisinin-interacting proteins from human nasopharyngeal cancer cells.
Mol Biosyst. 2012; 8(4):1311-8.

Krauth-Siegel RL, Leroux AE. Low-molecular-mass antioxidants in parasites.
Antioxid Redox Signal. 2012; 17(4):583-607.

Fueller F, Jehle B, Putzker K, Lewis JD, Krauth-Siegel RL. High throughput screening against the peroxidase cascade of African trypanosomes identifies antiparasitic compounds that inactivate tryparedoxin.
J Biol Chem. 2012; 287(12):8792-802.

Eberle, C., Lauber, B. S., Fankhausen, D., Kaiser, M., Brun, R., Krauth-Siegel, R. L. and Diederich, F. (2011) Improved inhibitors of trypanothione reductase by combination of motifs: Synthesis, inhibitory potency, binding mode, and antiprotozoal activities. Chem. Med. Chem. 6, 292-301.

Roldán, A., Comini, M. A., Crispo, M., and Krauth-Siegel, R. L. (2011) Lipoamide dehydrogenase is essential for both bloodstream and procyclic Trypanosoma brucei. Mol. Microbiol. 81, 623-639.

Diechtierow, M. and Krauth-Siegel, R.L. (2011) A tryparedoxin-dependent peroxidase protects
African trypanosomes from membrane damage. Free Radic. Biol. Med. 51, 856-868.

Ceylan S, Seidel V, Ziebart N, Berndt C, Dirdjaja N, Krauth-Siegel RL. The dithiol glutaredoxins of african trypanosomes have distinct roles and are closely linked to the unique trypanothione metabolism.
J Biol Chem. 2010; 285(45):35224-37.

Bakker BM, Krauth-Siegel RL, Clayton C, Matthews K, Girolami M, Westerhoff HV, Michels PA, Breitling R, Barrett MP. The silicon trypanosome.
Parasitology. 2010; 137(9):1333-41. Review.

Muhle-Goll C, Füller F, Ulrich AS, Krauth-Siegel RL. The conserved Cys76 plays a crucial role for the conformation of reduced glutathione peroxidase-type tryparedoxin peroxidase.
FEBS Lett. 2010; 584(5):1027-32.

Eberle C, Burkhard JA, Stump B, Kaiser M, Brun R, Krauth-Siegel RL, Diederich F. Synthesis, inhibition potency, binding mode, and antiprotozoal activities of fluorescent inhibitors of trypanothione reductase based on mepacrine-conjugated diaryl sulfide scaffolds.
ChemMedChem. 2009; 4(12):2034-44.

Comini MA, Dirdjaja N, Kaschel M, Krauth-Siegel RL.Preparative enzymatic synthesis of trypanothione and trypanothione analogues.
Int J Parasitol. 2009; 39(10):1059-62.

Wenzel IN, Wong PE, Maes L, Müller TJ, Krauth-Siegel RL, Barrett MP, Davioud-Charvet E. Unsaturated Mannich bases active against multidrug-resistant Trypanosoma brucei brucei strains.
ChemMedChem. 2009; 4(3):339-51.

Stump B, Eberle C, Schweizer WB, Kaiser M, Brun R, Krauth-Siegel RL, Lentz D, Diederich F. Pentafluorosulfanyl as a novel building block for enzyme inhibitors: trypanothione reductase inhibition and antiprotozoal activities of diarylamines.
Chembiochem. 2009; 10(1):79-83.

Wendler A, Irsch T, Rabbani N, Thornalley PJ, Krauth-Siegel RL. Glyoxalase II does not support methylglyoxal detoxification but serves as a general trypanothione thioesterase in African trypanosomes.
Mol Biochem Parasitol. 2009; 163(1):19-27.

Ramos EI, Garza KM, Krauth-Siegel RL, Bader J, Martinez LE, Maldonado RA. 2,3-diphenyl-1,4-naphthoquinone: a potential chemotherapeutic agent against Trypanosoma cruzi.
J Parasitol. 2009; 95(2):461-6.

Cavalli A, Lizzi F, Bongarzone S, Brun R, Luise Krauth-Siegel R, Bolognesi ML.
Privileged structure-guided synthesis of quinazoline derivatives as inhibitors of trypanothione reductase.
Bioorg Med Chem Lett. 2009; 19(11):3031-5.

Krauth-Siegel RL. Redox signaling and regulation in biology and medicine.
(editors: Jacob BC and Winyard PG), book review in
ChemMedChem. 2009; 4:2123-2127.

Filser M, Comini MA, Molina-Navarro MM, Dirdjaja N, Herrero E, Krauth-Siegel RL. Cloning, functional analysis, and mitochondrial localization of Trypanosoma brucei monothiol glutaredoxin-1.
Biol Chem. 2008; 389(1):21-32.

Krauth-Siegel RL, Comini MA. Redox control in trypanosomatids, parasitic protozoa with trypanothione-based thiol metabolism.
Biochim Biophys Acta. 2008; 1780(11):1236-48. Review.

Buchholz K, Comini MA, Wissenbach D, Schirmer RH, Krauth-Siegel RL, Gromer S. Cytotoxic interactions of methylene blue with trypanosomatid-specific disulfide reductases and their dithiol products.
Mol Biochem Parasitol. 2008; 160(1):65-9.

Melchers J, Krauth-Siegel RL, Muhle-Goll C. 1H, 13C, and 15N assignment of the oxidized and reduced forms of T. brucei glutathione peroxidase-type tryparedoxin peroxidase.
Biomolecular NMR Assignments. 2008; 2:65-68.

Comini MA, Rettig J, Dirdjaja N, Hanschmann EM, Berndt C, Krauth-Siegel RL. Monothiol glutaredoxin-1 is an essential iron-sulfur protein in the mitochondrion of African trypanosomes.
J Biol Chem. 2008; 283(41):27785-98.

Melchers J, Diechtierow M, Fehér K, Sinning I, Tews I, Krauth-Siegel RL, Muhle-Goll C. Structural basis for a distinct catalytic mechanism in Trypanosoma brucei tryparedoxin peroxidase.
J Biol Chem. 2008; 283(44):30401-11.

Beig M, Bender F, Oellien F, Rohwer A, Gaßel M, Selzer P, Unden G, Krauth-Siegel RL. Trypanothione reductase: a target protein for a combined in silico and in vitro screening approach.
Flavins and Flavoproteins 2008 (Frago S, Gómez-Moreno C, Medina M eds) Prensas Universitarias Zaragoza. 2008; 5503-8.

Stump B, Eberle C, Kaiser M, Brun R, Krauth-Siegel RL, Diederich F. Diaryl sulfide-based inhibitors of trypanothione reductase: inhibition potency, revised binding mode and antiprotozoal activities.
Org Biomol Chem. 2008; 6(21):3935-47.

Comini MA, Krauth-Siegel RL, Flohé L. Depletion of the thioredoxin homologue tryparedoxin impairs antioxidative defence in African trypanosomes.
Biochem J. 2007, 402(1):43-9.

Melchers J, Dirdjaja N, Ruppert T, Krauth-Siegel RL. Glutathionylation of trypanosomal thiol redox proteins.
J Biol Chem. 2007, 282(12):8678-94.

Krauth-Siegel LR, Comini MA, Schlecker T. The trypanothione system.
Subcell Biochem. 2007, 44:231-51.

Schlecker T, Comini MA, Melchers J, Ruppert T, Krauth-Siegel RL. Catalytic mechanism of the glutathione peroxidase-type tryparedoxin peroxidase of Trypanosoma brucei.
Biochem J. 2007, 405(3):445-54.

Stump B, Kaiser M, Brun R, Krauth-Siegel RL, Diederich F. Betraying the Parasite's Redox System: Diaryl Sulfide-Based Inhibitors of Trypanothione Reductase: Subversive Substrates and Antitrypanosomal Properties.
ChemMedChem. 2007, 2(12):1708-1712.

Otero L, Vieites M, Boiani L, Denicola A, Rigol C, Opazo L, Olea-Azar C, Maya JD, Morello A, Krauth-Siegel RL, Piro OE, Castellano E, González M, Gambino D, Cerecetto H. Novel antitrypanosomal agents based on palladium nitrofurylthiosemicarbazone complexes: DNA and redox metabolism as potential therapeutic targets.
J Med Chem. 2006, 49(11):3322-31.

Lee B, Bauer H, Melchers J, Ruppert T, Rattray L, Yardley V, Davioud-Charvet E, Krauth-Siegel RL. Irreversible inactivation of trypanothione reductase by unsaturated mannich bases: a divinyl ketone as key intermediate.
J Med Chem. 2005, 48(23):7400-10.

Meiering S, Inhoff O, Mies J, Vincek A, Garcia G, Kramer B, Dormeyer M, Krauth-Siegel RL. Inhibitors of Trypanosoma cruzi trypanothione reductase revealed by virtual screening and parallel synthesis.
J Med Chem. 2005, 48(15):4793-802.

Werner C, Stubbs MT, Krauth-Siegel RL, Klebe G. The crystal structure of Plasmodium falciparum glutamate dehydrogenase, a putative target for novel antimalarial drugs.
J Mol Biol. 2005, 349(3):597-607.

Schlecker T, Schmidt A, Dirdjaja N, Voncken F, Clayton C, Krauth-Siegel RL. Substrate specificity, localization, and essential role of the glutathione peroxidase-type tryparedoxin peroxidases in Trypanosoma brucei.
J Biol Chem. 2005, 280(15):14385-94.

Krauth-Siegel RL, Bauer H, Schirmer RH. Dithiolproteine als Hüter des intrazellulären Redoxmilieus bei Parasiten: alte und neue Wirkstoff-Targets bei Trypanosomiasis und Malaria.
Angew Chem. 2005, 117:698-724.

Krauth-Siegel RL, Bauer H, Schirmer RH. Dithiol proteins as guardians of the intracellular redox milieu in parasites: old and new drug targets in trypanosomes and malaria-causing plasmodia.
Angew Chem Int Ed. 2005, 44(5):690-715.

Krauth-Siegel RL, Davioud-Charvet E. Trypanothione reductase and other flavoenzymes as targets of antiparasitic drugs.
Flavins and Flavoproteins 2005 (Nishino T, Miura R, Tanokura M, Fukui K Ed.)
ArchiTect Inc Tokyo. 2005, 867-76.

Irsch T, Krauth-Siegel RL.Glyoxalase II of African trypanosomes is trypanothione-dependent.
J Biol Chem. 2004, 279(21):22209-17.

Friemann R, Schmidt H, Ramaswamy S, Forstner M, Krauth-Siegel RL, Eklund H. Structure of thioredoxin from Trypanosoma brucei brucei.
FEBS Lett. 2003, 554:301-305.

Schmidt H, Krauth-Siegel RL. Functional and physicochemical characterization of the thioredoxin system in Trypanosoma brucei.
J Biol Chem. 2003, 278(47): 46329-36.

Müller S, Liebau E, Walter RD, Krauth-Siegel RL. Thiol-based redox metabolism of protozoan parasites.
Trends Parasitol. 2003, 19(7):320-8.

Krauth-Siegel RL, Meiering SK, Schmidt H. The parasite-specific trypanothione metabolism of trypanosoma and leishmania.
Biol Chem. 2003, 384(4):539-49.

Krauth-Siegel RL, Inhoff O. Parasite-specific trypanothione reductase as a drug target molecule.
Parasitol Res. 2003, 90 Suppl 2: 77-85.

Gutierrez-Correa J, Krauth-Siegel RL, Stoppani AO. Phenothiazine radicals inactivate Trypanosoma cruzi dihydrolipoamide dehydrogenase: enzyme protection by radical scavengers.
Free Radic Res. 2003, 37(3):281-91.

Werner C, Stubbs MT, Klebe G, Krauth-Siegel RL. The crystal structure of lipoamide dehydrogenase from Trypanosoma cruzi: A target for the design of new drugs against Chagas’ disease.
Flavins and Flavoproteins 2002, :917-922

Shahi SK, Krauth-Siegel RL, Clayton CE. Overexpression of the putative thiol conjugate transporter TbMRPA causes melarsoprol resistance in Trypanosoma brucei.
Mol Microbiol. 2002, 43(5):1129-38.

Breidbach T, Scory S, Krauth-Siegel RL, Steverding D. Growth inhibition of bloodstream forms of Trypanosoma brucei by the iron chelator deferoxamine.
Int J Parasitol. 2002, 32(4):473-9.

Krauth-Siegel RL, Schmidt H, Trypanothione and tryparedoxin in ribonucleotide reduction.
Methods Enzymol. 2002, 347:259-66.

Schmidt H., Schmidt A., Krauth-Siegel RL. Der parasitäre Trypanothion-Stoffwechsel-einzigartig und lebensnotwendig.
BIOforum. 2002, 7-8:478-480.

Schmidt A, Clayton C, Krauth-Siegel RL. Silencing of the thioredoxin gene in Trypanosoma brucei brucei.
Mol. Biochem. Parasitol. 2002, 125:207-210

Reckenfelderbäumer, N., Krauth-Siegel, R. L. Catalytic properties, thiol pK value, and redox potential of Trypanosoma brucei tryparedoxin. J. Biol. Chem. 2002, 277, 17548-17555.

Inhoff, O., Richards, J. M., Briet, J. W., Lowe, G., Krauth-Siegel, R. L. Coupling of a competitive and an irreversible ligand generates mixed type inhibitors of Trypanosoma cruzi trypanothione reductase. J. Med. Chem. 2002, 45, 4524-4530.

Schmidt, A., Krauth-Siegel, R. L. Enzymes of the trypanothione metabolism as targets for antitrypanosomal drug development. Current Topics Med. Chem. 2002, 2, 1239-1259.

Dormeyer, M., Reckenfelderbäumer, N., Lüdemann, H., Krauth-Siegel, R. L. Trypanothione-dependent synthesis of deoxyribonucleotides by Trypanosoma brucei ribonucleotide reductase. J. Biol. Chem. 2001, 276, 10602-10606.