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Valorizing the Potential of South African Medicinal Plants-Discovery of new Natural Products Scaffolds as Leads against Neglected Tropical Diseases
Third-party funded project
Project title Valorizing the Potential of South African Medicinal Plants-Discovery of new Natural Products Scaffolds as Leads against Neglected Tropical Diseases
Principal Investigator(s) Hamburger, Matthias
Co-Investigator(s) Brun, Reto
Organisation / Research unit Departement Pharmazeutische Wissenschaften / Pharmazeutische Biologie (Hamburger)
Project start 01.01.2009
Probable end 31.12.2012
Status Completed
Abstract

The overall goal of the project is to discover natural product based leads acting against the parasites of some neglected infectious diseases such as malaria, leishmaniasis and trypanosomiasis. The discovery of such molecules is the starting point for the development of new and improved pharmacotherapy for these diseases, and to a reduction in the number of fatalities and disabilities associated with these diseases in poor and disease endemic countries (DEC). Based on an initial screening of a focused extract library, natural products with scaffolds new for the disease and promising in vitro activity will be identified in a miniaturized approach. Selected compounds will undergo further testing up to the stage of proof of in vivo activity in rodent models. These molecules are subsequently to serve as new lead structures for preclinical development.

Starting point for this drug discovery effort is a selection of South African plants for which traditional uses and other information available at CSIR are indicative of potential activity in tropical parasitic diseases. Approx. 500 extracts produced at CSIR from these plants are formatted at the Institute of Pharmaceutical Biology (UNIBAS) into a focused extract library and screened at Swiss Tropical Institute (STI) in the medium throughput screens. All process steps in the screening and consecutive lead identification are miniaturized, in part automated, and based on the 96-well microtitre footprint. Prioritized extracts are submitted to HPLC-based activity profiling with microtiter-based fractionation of column effluent, and simultaneous on-line spectroscopic (PDA, ion-trap ESI and APCI-MS, and ESI-TOF) analysis and dereplication with the aid of natural product databases and other tools. The profiling approach will be carried out jointly between CSIR and UNIBAS, with bioassay support given by STI. Structure elucidation is supported, in case of peaks of interest, by NMR spectroscopy using a 1mm microprobe. Compounds of interest are isolated in a targeted manner and submitted to a full structural characterization, to assessment of important physico-chemical properties for drug-likeness, and to assessment of in vitro potency and selectivity. Few selected compounds with most promising properties are submitted to in vivo testing in rodent models

We anticipate the discovery of molecules with structural scaffolds new for these tropical diseases. The use of functional parasitic assays instead of biochemical screens for predefined molecular targets, combined with efficient tracking of activity and early dereplication enable the focussed identification of structurally novel molecules with possibly new and unexpected modes of action, and with a proof of concept for in vivo activity in disease relevant animal models. We expect to carry three compounds with different structural scaffolds to that stage. These molecules may serve as new drug leads to be fed into lead optimization and preclinical development programs.

Keywords Tropical diseases, drug discovery, natural products, malaria, trypanosomiasis, leishmaniasis
Financed by Swiss Government (Research Cooperations)

Cooperations ()

  ID Kreditinhaber Kooperationspartner Institution Laufzeit - von Laufzeit - bis
43802  Hamburger, Matthias  Reto Brun, Prof  Swiss Tropical Institute  13.08.2009  13.08.2012 
470287  Hamburger, Matthias  Maharaj Vinesh, Dr.  Center for Scientific and Industrial Research (CSIR), Pretoria  01.09.2009  31.08.2012 
   

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