个人简介

Dec. 2011 Habilitandin, Department of Chemistry and Pharmacy, Emil Fisher Center, Friedrich-Alexander University of Erlangen - Nürnberg 2011-2011 Senior Researcher/Independent Research group Leader, Department of Chemistry and Pharmacy, Emil Fisher Center, Friedrich-Alexander University of Erlangen - Nürnberg 2008-2010 Posdoctoral Researcher, Department of Chemistry and Pharmacy, Emil Fisher Center, Working Group of Prof. Dr. Peter Gmeiner, Friedrich-Alexander University of Erlangen - Nürnberg, Germany 2004-2007 Biomolecular Science Center, Burnett College of Biomedical Sciences, University of Central Florida, Orlando, USA: PhD in Biomolecular Sciences; Working Group of Dr. Annette Khaled 2002-2003 Research Assistant, Klinikum Großhadern of the Ludwig Maximilians University of Munich, Working Group of Prof. Dr. Michael Hallak 1999-2002 Faculty of Chemistry and Chemical Engineering, University of Maribor, Slovenia: Master of Science (chemical technology – chemistry of polymer membranes). 1999-1999 Phillips - University of Marburg, Department of Biology, Project Work, Working Group of Prof. Dr. Harald Plachter 1998-1998 Mississippi State University, Department of Biology, Summer Research, Working Group of Prof. Dr. Ronn G. Altig 1993-1998 Pedagogical Faculty, University of Maribor, Slovenia: Maribor, Slovenia; biology and chemistry; Degree: diploma (bachelor) degree in biology and chemistry 1989-1993 High School Programme: Celje, Slovenia; Sciences and mathematics

研究领域

Pharmacy and Food Chemistry

Chemokine receptors are G protein-coupled receptors (GPCRs), which regulate the immune cell trafficking and control a multiplicity of processes in health and disease, ranging from immunosurveillance to inflammation, and from viral infection to cancer. Small-molecular-weight compounds which disrupt cell migration appear particularly promising for the management and treatment of inflammatory diseases and cancer. Also viruses like HCMV encode viral G-protein coupled receptors (vGPCRs), which couple very efficiently to signalling networks, are often highly homologous with hosts’ chemokine receptors, and augment virus survival, host invasion and, in some cases, promote oncogenesis or cardiovascular disease. In the contrast to chemokines small synthetic ligands bind to the chemokine receptors at the allosteric site(s) inside the hydrophobic pocket formed by transmembrane helices. The mechanism of allosteric modulation raises the possibility of designing novel ligands, which differentially activate downstream signaling pathways and thus promote desired therapeutic action with reduced unwanted effects. To advance the understanding of the allosteric modulation of human and viral chemokine receptors, we focus our efforts on the identification of molecular determinants involved in the allosteric modulation of these receptors. With the combination of site-directed mutagenesis, novel allosteric modulators, mass spectrometry and various functional assays (ranging from measuring the activation of G proteins, changes in secondary messenger release/production, β arrestin 2 recruitment, receptor internalization and changes at the transcriptional level) we are able to show that it is essential to differentiate between chemical modifications that influence the affinity of the allosteric modulator from those that influence the cooperativity related to endogenous ligands, as these properties are not necessarily correlated. In some cases allosteric modulators may impose bias on the signaling of an orthosteric ligand. Additionally, these approaches will be coupled to the state-of-the-art spectroscopic methods to investigate the receptor dynamics and ligand-induced conformational changes in live cells and artificial systems. Up to day is not yet clear to what extend the effect of biased signaling can be exploited for therapeutic advantage. Because of that reason our ultimate goal is to identify highly selective allosteric modulators with biased signaling profile and excellent pharmacological properties for the testing in animal disease models.

近期论文

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SCHMIDT, D., BERNAT, V., BROX, R., TSCHAMMER, N.,* KOLB, P.*: Identifying Modulators of CXC Receptors 3 and 4 with Tailored Selectivity using Multi-Target Docking. ACS Chem. Biol., 2014, ASAP. doi: 10.1021/cb500577j. * - corresponding author TSCHAMMER, N.*, KENAKIN, T., CHRISTOPOULOS, A.: Allosteric modulation of Chemokine Receptors. In: Topics in Medicinal Chemistry, Springer Verlag, 2014. doi: 10.1007/7355_2014_82 * - corresponding author BERNAT, V., BROX, R. HAIMANOT ADMAS, T., TSCHAMMER, N.: Boronic acids as probes for investigation of allosteric regulation of the chemokine receptor CXCR3. ACS Chem. Biol., 2014, 9(11): 2664-2677. doi: 10.1021/cb500678c. TSCHAMMER, N.: Allosteric modulation of the G protein - coupled US28 receptor of human cytomegalovirus: Are the small-weight inverse agonists of US28 "camouflaged" agonists? Bioorg. Med. Chem. Lett., 2014, 24(16):3744-7. doi: 10.1016/j.bmcl.2014.06.082. KLING, R., TSCHAMMER, N., LANING, H., CLARK, T., GMEINER, P., Active-state model of a dopamine D2 receptor - Gαi complex stabilized by aripiprazole-type partial agonists. PLOS One, 2014. doi: 10.1371/journal.pone.0100069. CUMMING, P., MASCHAUER, S., RISS, P., TSCHAMMER, N., FEHLER, S., HEINRICH, M.R., KUWERT, T., PRANTE, O., Radiosynthesis and validation of 18F-FP-CMT, a phenyltropane with superior properties for imaging the dopamine transporter in living brain. J. Cereb. Blodd Flow Metab., 2014, 34: 1148-1156. doi:10.1038/jcbfm.2014.63. FEHLER, S., MASCHAUER, S., HÖFLING, S., BARTUSCHAT, A., TSCHAMMER, N., HÜBNER, H., GMEINER, P., PRANTE, O., HEINRICH, M.R., Fast and efficient 18F-labeling via [18F]fluorophenylazocarboxylic esters. Chem. Eur. J., 2014, 20(2), 370-375. doi: 10.1002/chem.201303409. KRALJ,A., KURT, E., TSCHAMMER, N., HEINRICH, M., Synthesis and biological evaluation of novel biphenyl amides modulating the US28 receptor. ChemMedChem, 2014, 9(1): 151-168. doi: 10.1002/cmdc.201300369. KRALJ, A., NGUYEN, M.-T.,TSCHAMMER, N., OCAMPO, N., GESIOTTO, Q., HEINRICH, M., PHANSTIEL, O., Development of flavonoid-based inverse agonists of the key signaling receptor US28 of Human Cytomegalovirus. J. Med. Chem, 2013, 6(12): 5019-5032. doi: 10.1021/jm4003457 SANNA, F., ORTNER, B., HÜBNER, H., LÖBER, S., TSCHAMMER, N., GMEINER, P., Discovery of dopamine D4 receptor antagonists with planar chirality., Bioorg. Med. Chem., 2013, 21(7): 1680-1684. [doi:10.1016/j.bmc.2013.01.065] TSCHAMMER, N., Virally encoded G protein-coupled receptors: Overlooked therapeutic opportunities? In: Annual Reports in Medicinal Chemistry, Vol. 47, Academic Press, 2012, 379-392. ISSN 0065-7743. BERNAT, V., HEINRICH, M., BAUMEISTER, P., BUSCHAUER, A., TSCHAMMER, N., Synthesis and application of the first radioligand targeting the allosteric binding pocket of chemokine receptor CXCR3. ChemMedChem, 2012, In Press. doi:10.1002/cmdc.201200184 KRALJ, A., WETZEL, A., MAHMOUDIAN, S., STAMMINGER, T., TSCHAMMER, N., HEINRICH, M., Identification of novel allosteric modulators for the G-protein coupled US28 receptor of human cytomegalovirus. Bioorg. Med. Chem. Lett., 2011, 21, 5446-5450. doi:10.1016/j.bmcl.2011.06.120 KOSCHATZKY, S., TSCHAMMER, N., GMEINER, P., Cross-receptor interactions bewteen dopamine D2L and neurotensin NTS1 receptors modulate binding affinities of dopaminergics. ACS Chem. Neurosci., 2011, 2, 308-316, doi:10.1021/cn200020y EINSIEDEL, J., HELD, C., MAUD, H., PLOMER, M., TSCHAMMER, N., HÜBNER, H., GMEINER, P., Discovery of highly potent and NTS2 selective neurotensin mimetics. J. Med. Chem., 2011, 54, 2915-2923, doi:10.1021/jm200006c TSCHAMMER, N., ELSNER, J., GÖTZ, A., EHRLICH, K., SCHUSTER, S., RUBERG, M., KÜHHORN, J., THOMPSON, D., WHISTLER, J., HÜBNER, H.,GMEINER, P., Highly Potent 5-Aminotetrahydropyrazolopyridines: Enantioselective Dopamine D3 Receptor Binding, Functional Selectivity, and Analysis of Receptor-Ligand Interactions, J. Med. Chem., 2011, 54, 2477-2491, doi:10.1021/jm101639t LÖBER, S., HÜBNER, H., TSCHAMMER, N., GMEINER, P., Recent advances in the search of D3 and D4 selective drugs: probes, models and candidates, Trends in Pharm. Sci. 2011, 32(3), 148-157, doi:10.1016/J.TIPS.2010.12.003 TSCHAMMER, N., BOLLINGER, S., KENAKIN, T., GMEINER, P., Histidin 6.55 is a major determinant of ligand biased signaling in dopamine D2L receptor. Mol. Pharmacol. 2011, 79(3), 575-585. doi:10.1124/mol110.068106 KITTIPATARIN, C., TSCHAMMER, N.,KHALED, A.R., The interaction of LCK and the CD4 co-receptor alters the dose response of T-cells to interleukin-7. Immunol. Lett., 2010, doi:10.1016/j.imlet.2010.04.007. TSCHAMMER, N., DÖRFLER, M., HÜBNER, H., GMEINER, P., Engineering a GPCR-ligand pair that stimulates the activation of D2L by dopamine. ACS Chemical Neuroscience, 2010, 1,25-35. doi:10.1021/jcn900001b