Compounds of natural origin are the single most important source for inspiration in the development of new drugs. They can either be used as such, or serve as starting point for synthetic efforts. The aim of the project is to identify new molecules from higher plants and fungi acting against clinically relevant targets in important disease areas. These are in the fields of tropical diseases, CNS disorders, and inflammation and cancer.
The Institute of Pharmaceutical Biology has established a technology platform which enables the discovery process to be miniaturized and, to a certain degree, automated. The use of certain technology standards allows efficient cooperation and data exchange with collaborating partners.
Starting point of the project is a focussed in-house library of over 1000 extracts from higher plants and entomogenous fungi. The samples have been previously selected on the basis of ethnomedicinal uses, and chemotaxonomic and chemo-ecological considerations. Screening and subsequent follow-up of active extracts is carried out in the 96-well microtitre format, supported by a 2D barcoded sample management. Localization of bioactivity in extracts is carried out with the aid of HPLC-based activity profiling. This approach links high-performance separation with structural information recorded on-line, eg. UV and MS data, with biological information from the bioassays. Compounds of interest can be localized in the extract starting with mg-amounts of material. Further structure elucidation of active compounds is carried out with the aid of microprobe NMR spectroscopy, which allows spectra to be measured with mg-amounts of the natural product obtained by HPLC.
Only for compounds of major interest a preparative purification will be carried out in a highly targeted and, therefore, efficient manner. Isolation will be performed using a broad spectrum of modern separation technologies available at the institute, such as LPLC, MPLC, semiprep. HPLC, and centrifugal partition chromatography (CPC).
The search for compounds acting on protozoan parasites is carried out in a collaboration with the Swiss Tropical Institute. Screening for natural products modulating the activity of secretases and for PI3K class III inhibitors is performed in house, and in a local collaboration at the University of Basel. Profiling for GABAA receptor ligands, and inducers and inhibitors of angiogenesis and lymphangiogenesis is with partners at the University of Vienna and ETH Zürich. Further pharmacological characterization, eg. determination of IC50, Ki, selectivity, and in vivo activity will be determined for selected compounds.
We anticipate the discovery of a number of new structural templates which may serve as drug leads and/or as tools for basic biomedical research. |
