Research

Main research of this group is in the range of biochemical and bioorganic reserach and includes ligand receptor interactions of neuropeptides, signal transduction, protein expression and modification by ligation strategies as well as carrier peptides. Following topics are handled:

G-Protein Coupled Receptors: Identification of Ligand Binding

Prof. Dr. Annette G. Beck-Sickinger

Dr. Jan Stichel; Dr. Anette Kaiser; Dr. Rene Meier; M. Sc. Kerstin Burkert; M. Sc. Tristan Zellmann; M. Sc. Biochem. Mario Schubert; M. Sc. Biochem. Lisa KöglerM. Sc. Biochem. Mario Schubert; M. Sc. Biochem. Lisa Kögler

G protein coupled receptors are addressed by a number of different physiological ligands, such as neuropeptides and hormones. In this project, binding of agonists and antagonists to the G protein coupled receptors of neuropeptide Y, PP, PYY, RF-amide peptides, chemokines, and ghrelin are characterized on a structural level. Based on these results, improved analytical systems shall be developed that allow fast ligand screening. In addition, positive modulators are of great interest due to the high therapeutic potential of the ligand-receptor systems. Beside receptor expression in eukaryotic systems, receptors are expressed by in vitro translation as well as in bacterial systems, and recombinantly produced receptors are characterized.

Financial Support: DFG/NSF (BE1264-16), NIH, BMBF, ESF
Collaboration: Prof. Dr. D. Huster, Univ. Leipzig, Med. Fakultät; Prof. Dr. T. Schöneberg, Univ. Leipzig, Med. Fakultät; Prof. Dr. A. Robitzki, Univ. Leipzig; Prof. Thue W. Schwartz, Rigshospitalet Copenhagen; Prof. Jens Meiler, Vanderbilt University Nashville, TN; Intana Pharma GmbH, Prof. Roland Brock, Univ. Nimwegen, NL.

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Signaling Cascades of G-Protein Coupled Receptors

Prof. Dr. Annette G. Beck-Sickinger

Dr. Karin Mörl, Dr. Stefanie Babilon; Dr. Anette Kaiser; M. Sc. Biochem. Lizzy Wanka; M. Sc. Biochem. Stefan Ernicke; M. Sc. Biochem. Lisa Kögler

The intracellular trafficking, biosynthesis and internalization processes of G protein-coupled receptors are the focus of this project. We aim at a molecular characterization and understanding of the prerequisites for triggering and termination of specific signaling cascades. In this respect, we have already gained substantial insights for the internalization processes of the neuropeptide Y2 receptor. We focus on binding of different G proteins and arrestins, and receptor-specific differences are analyzed.

Financial Support: DFG (SFB 1052/A3), ESF
Collaboration:
Prof. Dr. D. Huster, Univ. Leipzig, Med. Fakultät; Prof. Dr. T. Schöneberg, Univ. Leipzig, Med. Fakultät; Prof. Jens Meiler, Vanderbilt University Nashville, TN; Prof. Seva Gurevich, Vanderbilt University Nashville, TN; Prof. Heidi Hamm, Vanderbilt University Nashville, TN.

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Molecular Mechanisms of Adipokines and Application Novel Therapeutics

Prof. Dr. Annette G. Beck-Sickinger

Dr. Karin Mörl; M. Sc. Biochem. Tobias Leimer; M. Sc. Biochem. Tom-Marten Kilian; M. Sc. Chem. Andreas Mattern; M. Sc. Biochem. Stefanie Wittrisch; Dipl. Pharmazeutin Cathleen Jendrny

In this project, the molecular basis of obesity is investigated interdisciplinarily. Genes related to the predisposition to obesity are identified and their gene products are characterized. In particular, ligand binding and signal transduction of DLK1, adiponectin, vaspin, and chemerin have been studied intensively. We were able to show that vaspin and chemerin act differently.

Financial Support: DFG (SFB 1052/ A3, C2); IFB K-17, K-59, GIF; Fond Chemischer Industrie
Collaboration: Prof. Dr. Wieland Kiess, Med. Fakultät, Univ. Leipzig; Prof. Dr. M. Blüher, Med. Fakultät, Univ. Leipzig; Prof. Dr. M. Stumvoll, Med. Fakultät, Univ. Leipzig; Prof. Dr. J. Simon, Med. Fakultät, Univ. Leipzig.

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Artificial Proteins in Intelligent Materials: Specific Immobilization of Molecules and Cells on Surfaces

Prof. Dr. Annette G. Beck-Sickinger

Dr. Kathrin Bellmann-Sickert; M. Sc. Chem. Mareen Pagel; M. Sc. Biochem. Sarah Zernia; M. Sc. Florian Ott 

Specific immobilization of peptides and proteins to surfaces is the focus of this project. For this purpose, chemically modified redox-proteins are generated and analyzed with respect to their bioenergetic properties. Immobilization of proteins, covalent attachment of co-substrates, incorporation of specific spacer groups and electron transfer molecules are being worked on. Enzymes, such as sortase, were used as model proteins and characterized. Proteins are expressed recombinantly as thioesters, modified by chemical ligation and immobilized specifically. Peptides used for immobilization have been developed rationally or by combinatorial approaches, and were optimized with respect to binding to certain surfaces, such as SiO2 or titanium oxide. Further, we were able to selectively release specifically immobilized proteins.

Financial Support: Graduiertenschule BuildMoNa, BMBF
Collaboration:
Prof. Dr. A. Robitzki, Institut für Biochemie, Univ. Leipzig; Prof. Grundmann, Fakultät für Physik und Mineralogie, Univ. Leipzig; Prof. Janke, Fakultät für Physik und Mineralogie, Univ. Leipzig; Prof. Dr. J. Käs, Fakultät für Physik und Mineralogie, Univ. Leipzig; Prof. Abel, Fak. Chemie und Mineralogie, Univ. Leipzig; Prof. Sträter, Fak. Chemie und Mineralogie, Univ. Leipzig; c-LEcta Leipzig.

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Selective Labelling of Peptide Hormones for Therapeutic and Diagnostic Application of Tumors

Prof. Dr. Annette G. Beck-Sickinger

Dr. Sylvia Els-Heindl; Dr. Sven Hofmann; Dipl. Biol. Katja Kostelnik; M. Sc. Chemie David Böhme; M. Sc. Dennis Worm

Selective peptide ligands and the corresponding GPCRs are applied as a carrier shuttle system for diagnosis and theraphy in cancer. Therefore, neuropeptides of the NPY family were conjugated with chelators and not radiactive isotopes. Different chelator structures as well as different position for the modification weren investigated.
For therapeutic applications the peptides were linked to cytostatics and carboboranes. Selectivity and toxicity of these constructs were tested in different tumor cell cultures. The therapeutic index could be determined by animal models. Futhremore, tumor accessibility of the peptide drug conjugates were investigated in 2D/3D tumor tissue models. Analysis of the proteome by mass spectrometry is applied to examine the effect on cell metabolism. Additionally, biophysiological methods were applied to determine the effect of the peptide drug conjugates on the stiffness of tumor tissue.

 

Financial Support: DFG (FOR 630/BE 1264-10); BMBF, EFRE, ESF, Industry
Collaboration: Prof. O. Prante, Univ. Erlangen; Dr. Irfan Khan, Islamabad, Pakistan; Prof. E. Hey-Hawkins, Fakultät für Physik und Mineralogie, Univ. Leipzig; Prof. J. Käs, Fakultät für Physik und Mineralogie, Univ. Leipzig; Prof. Dr. Martin von Bergen, Helmholtzzentrum für Umweltforschung

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Peptide and Protein Therapeutics

Prof. Dr. Annette Beck-Sickinger

Dr. Sylvia Els-Heindl; Dipl. Biol. Ria Schönauer; Dipl. Pharm. Cathleen Jendrny; M. Sc. Chemie Milos Erak; M. Sc. Jan-Patrick Fischer

Since their less biostability, peptides and proteins were not primarly focused as potential therapeutics. Now, new techniques as lipidation and pegylation could overcome these limitations. In the project, peptides for different indications are under investigation. The peptides are synthesized as conformationally restricted variants and with different modifications. Furthermore, the effect of these modifications on activity, stability and bioaccessibility is investigated.

Financial Support: TG 51, Industry
Collaboration:
Prof. Helen Cox, Kings College London; Industry.

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Chemical Modification of Proteins for the Characterization of Matrix-Protein Interactions

Prof. Dr. Annette G. Beck-Sickinger

Dr. Kathrin Bellmann-Sickert; M. Sc. Chemie Mareen Pagel; M. Sc. Biochem. Nydia Panitz; M. Sc. Chem. Andreas Mattern

Specific immobilization of protein mediatos improves the biocompatibility of implants with the natural tissue. In this project, mediators were modified with segments of the extracellular matrix and coupled to solid surfaces through specifically binding proteins. To estimate the inflammatory potential of implants, its interaction with chemokines and the effect of the implant on the chemokine release of cells are examined. The natural and modified chemokines, f.e. Interleukin-8 and SDF-1, are produced and investigated for their interaction with ECM-components.

Financial Support: DFG (TRR 67, TP A4)
Collaboration: Prof. Simon, Hautklinik, Med. Fakultät, Univ. Leipzig; Prof. D. Huster, Med. Physik, Med. Fakultät, Univ. Leipzig; Prof. Mayte Pisabaro, Biotec Dresden; Prof. D. Scharnweber, Max Bergmannzentrum TU Dresden; Dr. U. Hempel; Physiol. Chemie, Med. Fakultät, TU Dresden; Prof. Carsten Werner, IPF Dresden.

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Selective Bioconjugation of Proteins in Live Cells via Peptide-Directed Acyl and Alkyl Transfer Reactions

Prof. Dr. Annette G. Beck-Sickinger

Dr. Katrin Mörl; M. Sc. Biochem. Jonathan Lotze

Selective modification of proteins often is a critical step in biochemical research, because of slow reaction rates and small yield. Based on a template-mediated approach, the selectivity and speed of the labeling reaction could be significantly increased. In this project, this technique is investigated for soluble as well as transmembrane proteins.

Financial Support: DFG SPP 1263 (BE 1264/15-1)
Collaboration: Prof. Dr. O. Seitz, Humboldt-Universität Berlin

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last modified: 24.08.2016