SPEAKER

Integrating single bead, single compound, single molecule, & single cell technologies into a chemical genomics target validation process

All drugs on the market act on less than 250 proven targets from only 6 major target classes. The decomposition of the human genome followed by several years of functional genomics and proteomics research has so far not shown the expected impact in increasing the number of successfully tackled drug targets.... (more)

Systems Biology approaches to drug discovery and gene function

One of the grand challenges in the future of genomics research is the need to develop computational and experimental methods to detect gene-gene and gene-environment interactions for identifying the genetic contributions to disease and drug response. Scientists have been successful in cataloguing genes through genome sequencing projects, and we can now generate vast quantities of gene expression data using microarrays. However, the biology community has had far less success in understanding how genes and proteins are connected and operate within networks. When a cell is perturbed (whether by a drug or in a disease state), it is important to understand how it will respond in terms of gene expression and protein interactions...(more)

Microarray technology: new concepts and technologies

Understanding of complex functional mechanisms requires global and parallel analysis of cellular processes. Microarrays are a synonym for this kind of study and, in many cases, the obvious platform to such end. They have already made important contributions, although the true potential that is inherent to the technology is far greater. I will present new processes that are aiming at analysing in a quantitative manner protein interactions with other molecules (proteomics), at combining different levels of analysis on a single platform (biomedical diagnostics) and the production of biomolecules (synthetic biology) ... (more)

Chemical and Biological Sensors to Measure Protein Secretion in Yeast

The in vivo characterization of protein activities, key metabolites and other important parameters has become one of the central quests in molecular cell biology. The development and applications of tools that allow visualizing these parameters in living cells is therefore a highly active and interdisciplinary area of biological and chemical research. One of the goals of these activities is to obtain quantitative data on cellular processes in living cells and thereby to complement the more traditional analyses with a new in vivo biochemistry... (more).

Expanding the Frontiers of Organic Synthesis by Engineered and Biology-Based Concepts

The key role of Chemistry is still the chemical alteration and manipulation of molecules and materials. This feature of chemistry is commonly termed synthesis. Currently, it becomes evident that organic synthesis is expanding its tool box by implementing technologies from neighbouring fields such as engineering and biology into its portfolio. Typical examples are the use of enabling techniques such as microwave assistance and new reactor designs as well as molecular biology and engineered organisms...(more).

Tools for HTS data analysis, documentation and library design

Screening for bioactive small molecules in compound collections ranging from 20.000 to several hundred thousands and the design of libraries requires informatic tools which are not common for academic research. The ChemBioNet already tested appropiate software tools and defined standards for data exchange, library set up and analysis of screening data. A shared compound collection has been designed on the basis of the World Drug Index by drug design and modelling experts of the network. Tools and results will be presented here. The ChemBioNet pursues an  extension of the open screening platforms and resources for Chemical Biology to an European network combining regional expertise for support of primarily academic research projects. Concept, actual status and perspectives will be outlined... (more).

Chemical Biology and Chemogenomics in Drug Discovery

Chemical biology and chemogenomics are recent strategies in the systematic search for new lead structures. Chemical biology studies the influence of chemical libraries on biological systems, e.g. stem cells, yeast and other cellular systems, parasites, or small animals, like Caenorhabditis elegans, Drosophila or the zebrafish, Danio rerio. If a new phenotype is discovered by the action of a certain substance, the next step is the identification of the respective target... (more).

Biology Oriented Synthesis (BIOS) for Chemogenomics

The identification of small molecules that interact with the products of genome and modulate their biological function is at the heart of Chemogenomics, Chemical Biology, and medicinal chemistry research. The initial screening results from various libraries have made it clear that the structures of the compounds libraries need to be relevant in biological context and that the quality and not just quantity of the library members determine the hit rates... (more)

Practical Methods for the Stereoselective Synthesis of Bioactive Amines

Chiral amines are key structural elements in bioactive natural products and pharmaceuticals rendering their synthesis an objective of high priority from the perspective of natural product chemistry and drug discovery.[1] Our research programmes are directed towards the development of novel - in comparison to known procedures more direct and effective - methods to synthesize chiral amines in only one chemical, stereoselective transformation from ketones as readily available building blocks ('direct asymmetric reductive amination')... (more).

Chemoproteomics in Protein Kinase Inhibitor Discovery: From Targets to Compounds to Targets

Today’s target proteins of pharmaceutical relevance cluster into multi-member gene families, thus offering medicinal chemistry a systematic approach to broadly exploit once established agonist, antagonist, or inhibitor concepts. In this context, the family of protein kinases emerged as one, if not the most prominent target class for modern drug discovery and development, convincingly proven by the recently launched kinase inhibitors.... (more)

Universal Surface Chemistry for Capturing Small Molecules Without Linkers on Glass Slides

An ideal way of deploying the small molecule or chemical microarrays platform would be in ways that circumvent the preparation of specific small molecule libraries, thus eliminating the typically tedious synthetic effort needed to incorporate a tag/linker in the molecules. We have pursued several different types of chemistries for covalent attachment of small molecules to glass microscope slides with success... (more)

Encoded Self-Assembling Chemical Libraries, a Novel Tool in Drug Discovery

The de novo discovery and development of selective drugs for the multitude of protein targets originating from functional genomic research is a challenging task. Biochemical display technologies (such as phage display [1, 2] and ribosome display[3]) can be used for the isolation of polypeptides (e.g. antibodies) against virtually any given target. The success of these technologies relies mainly on the physical linkage between phenotype and genotype which allows the production of libraries of very large size and the possibility to identify binding library members from a simple affinity-based panning experiment, after performing an amplification step... (more).

POSTER

1

Dr. Bernhard Ay
Charité Berlin

Synthetic Peptide Arrays:
Chemical Production for Biological Applications

The possibility of synthesizing large addressable arrays of peptides is explored in basically two formats: macro- and microarrays. The former approach consists in the in situ solid-phase synthesis of peptides on cellulose membranes using the automated SPOT technology. This approach can be carried out with two scopes:.... (more)

2

Ines Block
DKFZ, Heidelberg

High Complexity Peptide Libraries on a Microchip

We present a novel approach for the combinatorial synthesis of high complexity peptide arrays utilizing amino acid particles. These microparticles comprise the activated, proteinogenic amino acids and can be charged by friction. This allows the consecutive addressing of monomer packages by means of electrostatic charged patterns generated on a solid support, where they are melted to release and couple the amino acids to the surface. Charge patterns are generated on CMOS microchips equipped with an array of individually triggered pixel electrodes. Resolution of synthesis is only restrained by the size of the chip structures and the particles employed... (more)

3

Frank Christian
Leibniz-Institut fuer Molekulare Pharmakologie, Berlin

Targeting Compartmentalised cAMP-dependent Signalling Pathways with Small Molecules

Small organic molecules for targeted disruption of protein-protein interactions are valuable tools to study cellular signalling processes. Of particular interest are direct protein-protein interactions mediated by scaffolding proteins, which position protein kinases, protein phosphatases, phosphodiesterases and other signalling proteins at defined sites within cells. This compartmentalisation facilitates temporally and spatially coordinated cellular signalling and thereby specific responses of cells to  given external stimuli.... (more)

4

Prof. Dr. Hans-Peter Deigner
SIRS-Lab GmbH, Jena

In-vivo and in-vitro investigation of Asprin using pan genomic differential gene expression analysis

Aspirin is a non-steroid anti-inflammatory drug known to inhibit NF-kappaB activation and the expression of associated gene expression of e.g.  cyclooxygenase-2 (COX-2), iNOS, VCAM-1 and ICAM-1 (Jung et al., 2006) in aged rats. Aspirin is known to display a wide range of side-effects which can be partly explain by its action on many different key signaling components such as MCP-1, ROS and  AP-1 (Dragomir et al., 2006); scavenger receptor class B type I as well as promoting cholesterol efflux (Tancevski et al., 2006); metalloprotease 2 (Nicolae et  al., 2005), and apoptosis via BCL2 down-regulation... .(more)

5

Antonius Dikmans
HZI, Braunschweig

Advancement and application of high-density chemical micro-arrays to probe for protein drug interactions within SMP "Protein"

“Chemical biology” applies low molecular weight compounds (small molecules, SMs) as probes to activate or inactivate primarily the functions of the gene products, the proteins. Obviously, SM probe molecules are potential drug leads and, thus, “chemical genetics/genomics” studies directly link up to pharmaceutical drug development. The discovery of suitable chemical probes is more or less an empirical but yet systematic process which requires a set of prerequisites: access to competent compound collections, logistics and robotics for high-throughput screening (HTS), HTS compatible assays for the processes under investigation and the bio-/chem.-informatic tools for data evaluation... (more)

6

Gunnar Ehrlich
Leibniz Universtit of Hannover

The Total Synthesis of Tedanolide

Tedanolide, a highly cytotoxic 18-membered macrolide, was isolated in 1984 by Schmitz and co-workers from the Carribbean sponge Tedania ignis, also known as fire sponge. Its structure was assigned by X-ray crystal structure analysis. Because of their significant antitumor activity and their complex structure, tedanolide and its 13-deoxy analogue have attracted considerable synthetic attention over the past decade.... (more)

7

R. Fischer
HZI, Braunschweig

Quantitative Phosphoproteomics predicts Kinase Activities involved in E-cadherin signaling

518 human protein kinases and 107 protein phosphatases form an essential part of the cellular signaling network. Recent progress in proteomics allows the identification and quantitative analysis of phosphopeptides by LC-MS/MS and offers a new strategy to systematically re-analyze signaling pathways. E-cadherin is decisive for the formation of cell-cell contacts and tightly regulated during any kind of tissue morphogenesis..... (more)

8

Dr. Ronald Frank
HZI, Braunschweig

The Screening Facility of the Helmholtz Centre for Infection Research

The Helmholtz Centre for Infection Research has created an integrated research program that aims to discover, create and characterize new bioactive small molecules and to identify their cellular targets and mechanisms of activity: the “Chemical Pipeline”. Its goals will be achieved by exploring both natural and synthetic molecular diversity, combining research on natural products, analytical and synthetic chemistry, and combinatorial chemistry/biochemistry with new developments at the Centre in microbial pathogenesis and cell biology.... (more)

9

Dominic Janssen
Leibniz University of Hannover

Chivosazole A
Elucidation Of The Full Absolute Configuration

Chivosazole A (1) belongs to a family of 31-membered macrolides which were isolated from the myxobakterium Sorangium cellulosum by Höfle and co-workers at the GBF (German Research Centre for Biotechnology) in Braunschweig.  Its structure was established by mass spectrometry and NMR studies. However it was not possible to determine the configuration of the ten stereocentres in the molecule...... (more)

10

Jieun Jung
University of Konstanz

Synthesis and structural characterization of polyubiquitin conjugates using high resolution mass spectrometry

Modification of proteins by covalent attachment of ubiquitin plays a fundamental role in the control of many biological processes including cell cycle regulation, transcription, DNA repair, and apoptosis (1, 2). Ubiquitin contains 7 lysine residues each of which in principle could be used for polyubiquitin conjugations and chain formation. Importantly, recent evidence indicates that the actual lysine residue of ubiquitin used for ubiquitin-ubiquitin conjugation determines the biochemical/biological function of the respective polyubiquitin chain. Therefore, the synthesis and structural characterization of a series of chemically defined polyubiquitin chains that differ by the lysine residue used for ubiquitin-ubiquitin attachement is a major goal of the present work...... (more)

11

Corinna Lange
Leibniz Inst. for Nat. Prod. Research and Infection Biology

The Natural Products Pool – Joining Forces in Providing Compounds for Drug Discovery

The HKI Natural Products Pool with about 9.000 well defined natural compounds, including synthetic analogues, from more than 90 groups from academia worldwide has been used in industrial drug discovery for about ten years. Although the Natural Products Pool is a rather small library as compared to regular HTS-libraries, it represents a structural diversity similar to that of WOMBAT, a large dataset with nearly 76.000 known ligands for a vast variety of enzymes...... (more)

12

Nina Klippel
HZI, Braunschweig

Phagocytosis assay based on living Candida albicans for the detection of effects of chemicals on macrophage function

Phagocytosis is the first step of defence against infections from the innate immune system, as it is the process of internalization of pathogens by cells with phagocytic activity, such as macrophages, which is followed by pathogen killing and destruction. Thus, phagocytosis assays are used as assays for one function of the innate immune system. As fungal infections are of increasing relevance and phagocytic mechanisms are dependent on the pathogenic organism and its viability, we established a microtiter plate phagocytosis assay based on viable, fluorescence – labelled Candida albicans..... (more)

13

Timo Mayer
Eberhard-Karls-University of Tübingen

Design and synthesis of a “tag-free“ chemical probe for photoaffinity labeling

Photoaffinity labeling (PAL) is a frequently used, powerful biochemical method to investigate structural and functional properties of biological systems.The method is based on the affinity of ligands to receptors, and is especially useful where the application of crystallography or NMR is difficult...... (more)

14

Enrico Missner
Bayer HealthCare/Bayer Schering Pharma

Unveiling potential off-targets:
Comprehensive selectivity profiling of a novel multi-target protein kinase inhibitor by inhibitor affinity chromatography (IAC) using different strategies of immobilization

To obtain a selectivity profile of a novel high-affinity multi-target protein kinase inhibitor (Luecking et al. 63-77) beyond the limitations of protein kinase panel screenings a chemical proteomics approach was carried out. As described previously (Godl et al. 15434-39) an analogue of the compound provided with a linker was coupled to epoxy activated sepharose 6B (beads). .......(more)

15

Thorben Nawrath
TU Braunschweig

Biological activities of bacterial volatiles

Many bacteria emit volatile compounds, which with few exceptions have been largely neglected by natural product chemists. We have investigated volatiles emitted by various strains of different bacterial classes, using headspace analysis [1]. Five major classes of compounds, belonging to different biosynthetic groups, are produced by these bacteria, including fatty acid derivatives, aromatic compounds, pyrazines, (sesqui)terpenes, and sulfur compounds. The ecological reasons why these compounds are produced are mostly unknown, but chemical defense and communication come immediately to mind..... (more)

16

Nicola Rahm
Leibniz University of Hannover

The Total Synthesis of Chlorotonil A via Intramolecular Diels-Alder Reaction

Chlorotonil A (1) (Figure 1) was isolated from myxobacterium Sorangium cellulosum by Höfle et al. at the HZI (Helmholtz Centre for Infection Research, Braunschweig, Germany) in 2004. Its structure was determined by NMR studies and X-ray analysis. The biological potential of Chlorotonil A is currenly being evaluated. Its structural features, in conjunction with its potentially valuable biological activity in secondary metabolism, make it an attractive target for total synthesis...... (more)

17

Tobias Reinl
HZI, Braunschweig

Total Synthesis of the Marine Macrolactone (-)-Dictyostatin

Listeria monocytogenes, a food borne mammalian pathogen, exploits the c-Met-receptor tyrosine kinase pathway to induce its uptake into non-phagocytic cells. The listerial virulence factor Internalin B (InlB) is sufficient to activate c-Met after binding and to promote a massive actin filament rearrangement with the ultimate effect of internalization...... (more)

18

Hartmut Röhm
Eberhard-Karls-University of Tübingen

Total Synthesis of the Marine Macrolactone (-)-Dictyostatin

The macrolactone (-)-dictyostatin was first isolated by G. R. Pettit from a Maledives marine sponge Spongia sp. in 1994. In 2001 Wright and co-workers showed, that it strongly inhibits the growth of human cancer cells by stabilizing the microtubules preventing the depolymerisation to tubulin heterodimers..... (more)

19

Romy Schäckel
Leibniz University of Hannover

Towards the Total Synthesis of Disorazole Analogues

The Disorazoles are a structurally interesting family of 29 closely related macrocyclic dilactones. They were isolated in 1994 at the HZI in Braunschweig by Höfle and co-workers from the fermentation broth of the myxobacterium Sorangium Cellulosum (Strain So ce12).Their structures are modified in the carbon chain by variation of the position and configuration of double bonds and oxygen substituents like epoxide, hydroxyl, or methyl ether groups...... (more)

20

Iuliana Susnea
University of Konstanz

Identification of Chlamydia pneumoniae antigens via immuno-proteomics using high resolution FTICR mass spectrometry

Chlamydia pneumoniae is an important respiratory pathogen that causes approximately 5 % of all cases of bronchitis and it is believed to be responsible for about 10 % of the cases of community-aquired pneumonia. C. pneumoniae is an obligate intracellular bacteria with an unique life cycle alternating between an infectious but non-replicating elementary body (EB) and a non-infectious but metabolically active reticulate body (RB). More than 50 % of the adult European population has antibodies against C. pneumoniae..... (more)

21

Dr. Werner Tegge
HZI, Braunschweig

Screening synthetic and natural compounds for antimicrobial and anti-biofilm activities

Biofilm formation is of major importance in  the medical setting, whether it be in the context of infection processes like e.g. cystic fibrosis associated pneumonia or in the context of the infection of incorporated foreign materials, like e.g. artificial heart valves, artificial joints or catheters. In biofilms bacteria show resistance against antibiotics that is magnitudes higher than in an open environment... (more)

22

Verena Thiel
TU Braunschweig

Identification of bacterial signalling molecules

Cell-to-cell communication is used by bacteria to coordinate their behaviour and function in a cell-density-dependent manner. This phenomenon is termed quorum sensing. In general, Gram-negative bacteria use acylated homoserine lactones (AHLs) as autoinducers. Another signalling molecule is the so called autoinducer 2, the cyclic borate diester of 4,5-dihydroxy-2,3-pentanedione (DPD).... (more)

23

Gerald Wardenga
Leibniz University of Hannover

Total Synthetic Approach to Corallopyronin A and Analogue Structures

The corallopyronins were isolated in 1984 by Jansen et al. from the bacterium Corallococcus coralloides.[1] They are characterised by a remarkable activity against rifampin-resistant S. aureus.[2] All corallopyronins contain a 6-membered pyrone ring and a vinyl carbamate in the eastern part, whereas their structures differ in the western side chain...... (more)

24

Prof. Dr. U. Bilitewski
HZI, Braunschweig

Growth Characteristics and Stress Response Parameters of Yeasts Treated with Fungicidal Secondary Metabolites

Fungal infections are of increasing relevance in immunocompromised patients and Candida albicans plays a dominant role among the human fungal pathogens. This budding yeast has diverged from Saccharomyces cerevisiae lineage several million years ago, so that significant homologies but also differences in gene and protein functions can be expected.... (more)

25

Manuela Schüngel
HZI, Braunschweig

Development of peptides that inhibit the cellular invasiveness S. pyogenes and their testing in a new high-througput-assay

The human pathogen Streptococcus pyogenes, a gram-positive, spherical bacterial species, belongs to the group A streptococci (GAS). It causes several diseases that range from pharyngitis, scarlet fever, rheumatic fever to severe infections like toxic shock syndrome and necrotizing fasciitis [Molinari, G. & Chhatwal, G.S. (1999) Curr. Opin. Microbiol. (2) 56ff]..... (more)

26

Carsten Grötzinger
Charité, Berlin

Peptide Chips for Diagnostic Seroanalytics

The analysis of antibodies in serum is an established technique in the laboratory diagnosis of infectious as well as autoimmune diseases. Classical serological assays are based on immobilized antigens that serve to capture antigen specific antibodies from serum samples...... (more)