Drugs from Nature Targeting Inflammation

Projects

PP01: Coordination

Group: Hermann Stuppner, Institute of Pharmacy/Pharmacognosy, University of Innsbruck, CCB - Centrum of Chemistry and Biomedicine, Innrain 80-82/IV, 6020 Innsbruck, Austria
http://www.uibk.ac.at/pharmazie/pharmakognosie/

The main objectives of coordination project are documentation management, controlling the research process and its output, management and controlling of financial affairs, maintenance of the communication and the overall organization within the NFN like publications, presentations and dissemination. The coordination project will be the contact point for all members of the NFN. A steering committee will be formed to decide the NFN internals and to agree on a consortial agreement. Regular meetings for the NFN-members are planned. The necessary infrastructure is available.

PP03: From in Silico Plant Selection to the Bioactive Natural Products

Group: Hermann Stuppner, Judith Rollinger, Institute of Pharmacy/Pharmacognosy, University of Innsbruck,  CCB - Centrum of Chemistry and Biomedicine, Innrain 80-82/IV, 6020 Innsbruck, Austria
http://www.uibk.ac.at/pharmazie/pharmakognosie/

One of the major research interests at the Institute of Pharmacy/Pharmacognosy in Innsbruck is dedicated to the target-oriented search of bioactive plant constituents combining classical pharmacognostic methods (bioguided fractionation, ethnopharmacological approach) and modern in silico tools (pharmacophore based virtual screening). Promising plant material selected by in silico prediction and from ethnopharmacological hints are extracted and analytically investigated. Using LC-MS, GC-MS and especially LC-(SPE)-NMR, the bioactive constituents are tracked down in the plant matrix. Compounds of interest are isolated by semi- and preparative chromatographic methods and their structure is determined by mass spectrometry and NMR-spectroscopy. These compounds will be forwarded to the collaborating groups for evaluation of the anti-inflammatory potential.

PP04: From Cell-based Assays to Molecular Mechanisms

Group: Verena M. Dirsch, Atanas Atanasov, Elke H. Heiss, Department of Pharmacognosy, Pharmacology, Molecular Biology, University of Vienna, Althanstr. 14 (UZA II), 1090 Wien, Austria
http://www.univie.ac.at/pharmakognosie/ 

The major interest of the group is to identify bioactive natural products and to understand the molecular interaction of natural products with proteins/signaling molecules within cells. Thus, the task of PP04 within the NFN is to provide cell-based pharmacological models i) to contribute to bio-guided fractionation and isolation of active compounds; and ii) to do the pharmacological in-depth characterization of isolated hits in terms of their molecular mechanism of action. On one hand, the group will take over virtual hits isolated by cooperating groups and verify their predicted bioactivity. On the other hand, we will contribute to bio-guided fractionation of plants selected by ethnopharmacological criteria. For this, we provide cellular models that allow the screening and bio-guided fractionation of extracts aiming to isolate in vitro anti-inflammatory compounds (i.e. by luciferase reporter gene assays).

PP05: From Ethnomedicine to Bioactive NPs via Bioassay-Guided Isolation

Group: Rudolf Bauer, Franz Bucar, Wolfgang Schühly, Karin Wölkart, Institute of Pharmaceutical Sciences/Pharmacognosy, University of Graz, Universitätsplatz 4/I, 8010 Graz, Austria 
http://www.kfunigraz.ac.at/phgwww/

The major goal of the Institute of Pharmaceutical Sciences/Dept. Pharmacognosy, Karl-Franzens-University Graz is the isolation of active constituents from selected plant material from traditional Chinese medicine (TCM). Research includes pharmacognostic identification and phytochemical characterization (metabolic profiling) of the plant material. Active extracts will be fractionated using the concept of activity guided isolation in collaboration with partner groups. Fractionation and isolation will be achieved by applying preparative thin layer chromatography, column chromatography, medium pressure liquid chromatography, preparative HPLC and/or solvent partition chromatography. The structures of the compounds will be elucidated by spectroscopic means (UV, IR, MS, NMR). Identified compounds will be submitted to partner groups for in-silico screening and evaluation of the pharmacological anti-inflammatory potential. Additional pharmacological profiling can be done in both cellular (inhibition of leukotriene biosynthesis in human granulocytes and human platelets; inhibition of nitric oxide synthase (iNOS) in RAW 264.7 macrophages) and enzymatic (inhibition of prostaglandin biosynthesis by COX-1 and COX-2) in vitro assays.

PP10: Lead-Modification of Medicinal Plant Constituents and Synthetic Lead Up-scaling

Group: Marko D. Mihovilovic, Institute of Applied Synthetic Chemistry, Vienna University of Technology, Getreidemarkt 9/163, 1060 Vienna, Austria 
http://www.ias.tuwien.ac.at/ 

As new member of the already established consortium, the complementary expertise of this group in (bio)organic synthesis and medicinal chemistry will be implemented in order to further strengthen the composition of the network. One part of the contribution will focus on moderate structural modifications of established bioactive compounds as proposed by the consortium partners. Implementation of concepts from green chemistry especially focusing on streamlining synthetic routes by single-operations multiple-step transformations and continuous processes will be an integral part of this project part. Another aspect will be the synthesis and up-scaling of promising bioactive compounds. Access to plant-derived bioactive compounds is usually of limited efficiency based on extraction; in particular after structural modification (as outlined above) synthetic efforts have to be invested in order to provide access to sufficient quantities for in-depth biological studies.

PP11: Identification of bio-active natural products by virtual screening

Group: Daniela Schuster, Institute of Pharmacy/Pharmaceutical Chemistry/Computer Aided Molecular Design Group,  University of Innsbruck, CCB - Centrum of Chemistry and Biomedicine, Innrain 80-82/IV, 6020 Innsbruck, Austria
http://pharmazie.uibk.ac.at/camd/

The major research interest at the Computer Aided Molecular Design Group within the Institute of Pharmacy/Pharmaceutical Chemistry in Innsbruck is dedicated to the understanding and computer-assisted modeling of ligand-protein interactions. Using this approach, promising potentially biologically active molecules can be identified from large structure databases by performing in silico (virtual) screening experiments. In the framework of this NFN, we will apply and refine our methods for enhancing their efficiency in the field of natural products. The use of pharmacophore-based activity profiling will predict mechanisms of action of bioactive natural products. We will also perform binding mode predictions using flexible docking methods and virtual library design to support lead structure optimization studies within the NFN. Thereby, along with all NFN project partners, we are going to elucidate mode of actions of anti-inflammatory natural products and also help to develop more active compounds within the lead structure optimization branch of this nework.

PP13: In vitro and in vivo models for inflammation

Group: Valery Bochkov, Center of Biomolecular Medicine and Pharmacology, Department of Vascular Biology & Thrombosis Research, Medical University of Vienna, Schwarzspanierstr. 17, 1090 Vienna, Austria
http://www.meduniwien.ac.at/vascbio/

The aim of this project part is the evaluation of compounds identified in project parts 02, 03, 05 and 06 analyzed for their interference with the pro-inflammatory NFκB pathway in PP04 for their potential non- NFκB dependent anti-inflammatory activity using in vitro models and to evaluate all specified compounds in ex vivo as well as in vivo models. The main focus lies on the effectiveness of such compounds in acute and chronic, specifically chronic cardiovascular inflammatory models in  mice and on the analysis of “global” effects of natural compounds over and above of their possible specific targets such as the NFκB.
or the arachidonic acid metabolite pathways. It is hypothesized that in addition to their activity of nuclear receptors or by affecting epigenetics or micro-RNAs of target cells thereby influencing a broad spectrum of cellular pathways such as inflammation, metabolism, proliferation and survival.