Christian Eberle

 

PhD Student

Location: HCI G-306
Phone: +41-44-633 41 68
e-mail:

Christian Eberle

Education

2002-2006: Study of chemistry at ETH Zurich
2003 - 2004: ERASMUS exchange semester at the University of Cambridge, UK
2006: Master thesis with Prof. F. Diederich at ETH Zurich
2006 - 2007: Internship at F. Hoffmann-La Roche, Basel
since 2007: PhD with Prof. F. Diederich at ETH Zurich

Design, Synthesis, and Evaluation of Trypanothione Reductase Inhibitors as Potential Antiprotozoal Agents


Proposed binding mode for a fluorescent TR inhibitor in the active site of the enzyme.

Trypanosomatids are parasites that are the causative agents of African sleeping sickness, Chagas' disease and leishmaniasis. According to the WHO, these diseases constitute one of the most important health problems in the developing world. Trypanosomatids differ from nearly all other eukaryotes and prokaryotes in their specific sulfur redox metabolism, which is based on trypanothione and the flavoenzyme trypanothione reductase (TR). The trypanothione system, which replaces the nearly ubiquitous mammalian glutathione/glutathione reductase system, protects the parasites from oxidative damage and has been shown to be essential, rendering the enzyme a promising target for the development of new antiparasitic drugs. The disulfide binding site of TR is much wider than that of the closely related human glutathione reductase (hGR), making it difficult to develop low molecular weight compounds that bind selectively to the solvent exposed groove. The aim of this project is the design, synthesis and evaluation of novel TR inhibitors and the investigation of their binding mode.

Publications

C. Baumgartner, C. Eberle, F. Diederich, S. Lauw, F. Rohdich, W. Eisenreich, A. Bacher, Helv. Chim. Acta 2007, 90, 1043-1068. Structure-Based Design and Synthesis of the First Weak Non-Phosphate Inhibitors for IspF, an Enzyme in the Non-Mevalonate Pathway of Isoprenoid Biosynthesis.

B. Stump, C. Eberle, M. Kaiser, R. Brun, R. L. Krauth-Siegel, F. Diederich, Org. Biomol. Chem. 2008, 6, 3935-3947. Diaryl Sulfide-Based Inhibitors of Trypanothione Reductase: Inhibition Potency, Revised Binding Mode and Antiprotozoal Activities.

B. Stump, C. Eberle, W. B. Schweizer, M. Kaiser, R. Brun, R. L. Krauth-Siegel, D. Lentz, F. Diederich, ChemBioChem 2009, 10, 79-83. Pentafluorosulfanyl as a Novel Building Block for Enzyme Inhibitors: Trypanothione Reductase Inhibition and Antiprotozoal Activities of Diarylamines.

C. Eberle, J. A. Burkhard, B. Stump, M. Kaiser, R. Brun, R. L. Krauth-Siegel, F. Diederich, ChemMedChem 2009, 4, 2034-2044. Synthesis, Inhibition Potency, Binding Mode, and Antiprotozoal Activities of Fluorescent Inhibitors of Trypanothione Reductase Based on Mepacrine-Conjugated Diaryl Sulfide Scaffolds.

Last update: Dec. 2009