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Project E1 - Platform Fasciola, Filaria, Schistosoma, Echinococcus – knowledge transfer, compound screening

PI
PI
Project description

Background: Among the NTDs, infections with parasitic worms (helminths) cause the biggest threat to human health worldwide (over 10 million DALYs [disability-adjusted life years]). Major helminth-induced diseases are schistosomiasis, lymphatic filariosis, and infections with food-borne helminths (fasciolosis, echinococcosis, and others)1. The discovery of novel compounds to fight NTDs is of utmost urgency against the background of a limited spectrum of anti-parasitic drugs and missing vaccines, suboptimal therapeutic success, and upcoming or existing drug resistance.

e1
Fig. E1: Novel active compounds and drug candidates derived from DRUID projects will be tested for anti-helminthic broad-spectrum efficacy with the aid of in vitro test systems of national and international cooperation partners.

 

Targets of anti-parasitic substances are often conserved (e.g. β-tubulin, cathepsins, GPCRs), which renders the therapy of different parasitic infections with the same active compound possible. For instance, anti-malarial drugs such as mefloquine2 also showed toxic effects against schistosomes, and the groups Becker (B3) and Grevelding (B5) recently showed the same for arylmethylamino steroids3. We and others demonstrated a lethal effect of the tyrosine kinase inhibitor imatinib against different helminths with help of in vitro test systems, including the liver fluke Fasciola hepatica, the fox tapeworm Echinococcus multilocularis, and the blood fluke Schistosoma mansoni4,5,6. Whether dithiocarbamates, aldose reductases, and other substances for which we have demonstrated anti-schistosomal activity7,8 could act against other helminths as well is the subject of planned research activities. In this context, the availability of in vitro test systems of our cooperation partners enables the identification of substances with a wide range of anti-parasitic efficacy.

 

Scientific goals: Platform project E1 allows testing new compounds and drug candidates from DRUID projects against important helminth species. To this end, the expertise of external national and international cooperation partners will be integrated into DRUID. These partners have the required parasite life cycles, in vitrodrug testing systems (microcalorimetry, metacestode vesicle culture, filaria/insect cell-based assays), and animal models at their disposal. With the help of these test systems, microscopy, and histology, data will be obtained on the physiological and morphological effects of test substances in helminths (metabolic activity, tissue integrity) and vitality parameters (motility, survival). The aim is to identify substances with a broad anti-parasitic efficacy and discover conserved modes of action.

 

References E1: 1 WHO Global Health Observatory Data Repository for 2011; 2 Keiser et al. (2010) Clin Infect Dis 50:1205-13; 3* Krieg et al. (2017) Nat Commun 8:14478; 4 Manneck et al. (2013) J Clin Microbiol 49:1217-25; 5 Hemer und Brehm (2008) Int J Antimicrob Agents 40:458-62; 6* Beckmann S et al. (2010) Int J Parasitol 40:521-6; 7* Mäder et al. (2016) Chem Med Chem 11:1459-68; 8* Blohm et al. (2016) Parasitol Res 115:3831-42.

*own publications