Helmholtz Zentrum München – German Research Center for Environmental Health

Automation for high-throughput screening in the Assay Development and Screening Facility of HMGU (Source: HMGU)

HMGU focuses on common diseases that arise from the complex interplay of individual genetic predisposition and environmental factors. To this end, a professional portfolio management of early drug discovery projects aims to identify novel drugs that tackle innovative targets such as, for example, protein-protein interactions. Current drug discovery projects internally funded by HMGU are in the fields of diabetes, neurodegeneration, infectious diseases and cancer.

The HMGU has various facilities and platforms to support early drug discovery in vitro and in cells, including protein expression, assay development and screening, and structure-based drug discovery using NMR spectroscopy, and X-ray crystallography. The Assay Development & Screening Platform at HMGU develops in vitro and (sterile) cell-based assays including stem cells and iPS cells. A novel Metabolomic Validation Platform (metDRUG) helps to decide on safe and metabolic-tolerable drugs at early stages of development by quantifying metabolites indicative for key pathways.

The drug discovery projects are supported by structural biology expertise and infrastructure. The Bavarian NMR Center (BNMRZ), a joint research infrastructure between HMGU and the Technische Universität München (TUM) performs NMR structural study of proteins and protein-ligand interactions on the highest international level. The BNMRZ is a leading NMR centre in Germany and an important partner of the Helmholtz Association. HMGU provides NMR-monitored fragment-based screening, hit validation and structural analysis of target proteins with biologically active molecules.

The experimental work of HMGU research centres is supported by a number of research groups focused on theoretical research. They develop new in silico methodology for ADME/T models, annotated chemical libraries and virtual screening.

The German Mouse Clinic, a renowned scientific platform for standardized phenotyping of mouse-mutants and an important partner of ESFRI-Infrafrontier, explores the systemic side-effects of small molecules in mouse models for a better understanding of pharmacologic intervention in human diseases.

The successful transfer of research results into clinical application has been shown by the approval of Removab®, a biopharmaceutical drug for the treatment of malignant ascites originating from HMGU.

Technical University of Munich

The Department of Chemistry at the TU München (TUM) addresses fundamental questions of protein research including studies of molecular interactions of proteins with small molecules and bioactive compounds. It offers unique expertise in the field of biomolecular NMR spectroscopy and protein crystallography.

The biochemical research is imbedded in the CIPSM DFG Cluster of Excellence (Center for Integrated Protein Science Munich).

The Department of Chemistry exhibits outstanding internationally recognized competence in synthetic chemistry (method development and total synthesis of natural products) as well as biological and medicinal chemistry, such as structure-based design of peptidomimetics as inhibitors of integrin signalling or proteasome inhibitors.

 

 

Publications

Corsini L., Bonnal S., Basquin J., Hothorn M., Scheffzek K., Valcárcel J., Sattler M. U2AF-homology motif interactions are required for alternative splicing regulation by SPF45. Nat. Struct. Mol. Biol. (2007) 14: 620-629.

Ferch U., Kloo B., Gewies A., Pfänder V., Düwel M., Peschel C., Krappmann D., Ruland J. Inhibition of MALT1 protease activity is selectively toxic for activated B cell-like diffuse large B cell lymphoma cells. J. Exp. Med. (2009) 206: 2313-2320.

Kremb S., Helfer M., Heller W., Hoffmann D., Wolff H., Kleinschmidt A., Cepok S., Hemmer B., Durner J., Brack-Werner R. EASY-HIT: HIV full-replication technology for broad discovery of multiple classes of HIV inhibitors. Antimicrob. Agents Chemother. (2010) 54:5257-68. European Patent Nr. 101 30 155. US Patent Application Nr. 10/176,010.

Simon B., Madl T., Mackereth C.D., Nilges M.,  Sattler M. An efficient protocol for NMR-based structure determination of protein complexes in solution. Angew. Chem. Int. Ed. Engl. (2010) 49: 1967-1970.

Trivedi, C.M., Luo, Y., Yin, Z., Zhang, M., Zhu, W., Wang, T., Floss, T., Goettlicher, M., Noppinger, P.R., Wurst, W., Ferrari, V.A., Abrams, C.S., Gruber, P.J. and Epstein, J.A. Hdac2 regulates the cardiac hypertrophic response by modulating Gsk3 beta activity. Nat. Med. (2007) 13: 324-331.

Böttcher, T., Sieber, S.A. Showdomycin as a versatile chemical tool for the detection of pathogenesis associated enzymes in bacteria. J. Am. Chem. Soc. (2010) 132: 6964–6972.

Delgado O., Müller H. M., Bach T. Concise Total Synthesis of the Thiazolyl Peptide Antibiotic GE2270 A. Chem. Eur. J. (2008) 14: 2322-2339.

Doedens L., Opperer F., Cai M., Beck J. G., Dedek M., Palmer E., Hruby V. J., Kessler H. Multiple N-methylation of MT-II backbone amide bonds leads to melanocortin receptor subtype hMC1R selectivity; pharmacological and conformational studies. J. Am. Chem. Soc (2010) 132: 8115-8128.

Groll M., Schellenberg B., Bachmann AS., Archer CR., Huber R., Powell TK., Lindow S., Kaiser M. and Dudler R. A plant pathogen virulence factor inhibits the eukaryotic proteasome by a novel mechanism. Nature. (2008) 452: 755-758.

Hessling, M., Richter, K. & Buchner, J. Dissection of the ATP-induced conformational cycle of the molecular chaperone Hsp90. Nature Struct. & Mol. Biol. (2009) 16, 287 – 293; Patent: Hessling, M., Richter, K. and Buchner, J. Verfahren zur Identifizierung, Validierung und Optimierung von Hsp 90-Inhibitoren (2009) Patent PCT/EP 2009/061952.

Contact

  • Prof. Dr. Michael Sattler

    Institute of Structural Biology

    Helmholtz Zentrum München – German Research Center for Environmental Health

    Ingolstädter Landstraße 1
    85764 Neuherberg

    Phone: +49 89 3187-3800
    Fax: +49 89 3187-193800
    E-Mail: Contact

  • Prof. Dr. Thorsten Bach

    Department of Chemistry

    Technical University of Munich

    Lichtenbergstraße 4
    85747 Garching

    Phone: +49 89 289-13300
    Fax: +49 89 289-14386
    E-Mail: Contact