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Inhibitor analyses with Schistosoma mansoni in vitro

Inhibitor analyses with Schistosoma mansoni in vitro


Since the 1980s Praziquantel (PZQ) is regularly used as the only drug being able to kill all schistosome species. This provokes the fear of emerging resistance and motivates the search for alternatives. This project aims at specific molecules that were either identified as interesting targets in previous studies from our lab or from the analysis of the genome data of S. mansoni1. It concerns proteins with enzymatic function (not kinases), which are conserved in nature – such proteins have not experienced substantial changes during evolution. Furthermore, these proteins can be associated with specific human diseases. Hence pharmaceutically active substances (inhibitors) exist that inhibit the activity of such proteins.

In cooperation with the group of Prof. Schlitzer/Patrick Mäder (University Marburg, Germany) we investigate the effects of derivatives of such inhibitors using an established in-vitro model of schistosomes2-6. In cooperation with the group of Katja Becker (University Giessen, Germany), we test novel compounds with strong anti-protozoal effects for simultaneous anti-schistosomal activity7. Furthermore, we detected the anti-schistosomal in vitro effect of Harmonine, an alkaloid of the Lady beetle. This demonstrates the value of searching for antiparasitic/antimicrobial substances in insects8. Aim of these studies is to find effective substances acting schistosome-specific at low concentrations. In parallel, molecular and biochemical analyses are performed to unravel the meaning of the target proteins for schistosome biology. With this approach we hope to overcome existing limitations and to find alternative treatment options for schistosomiasis. Due to functional and structural similarities of the target molecules there is a realistic chance that appropriate inhibitor derivatives could also be applied to fight other worm parasites affecting the health of humans and animals, especially those that – from the perspective of evolution – are closely related to schistosomes, such as cestodes or liver flukes (see also project 7).


 

Arianes Inhibitoren 2.jpg

Observation of adult schistosomes in vitro by bright-field microscopy (left). In this exemplary case, the worms were treated with a specific inhibitor and subsequently lay on the side, get stiff, show reduced vitality and blowy excrescences at their tegumental surface (middle). In contrast, untreated worms are vital, they suck,   and they exhibit an intact tegumental surface (right).


1Berriman M, Haas BJ, LoVerde PT, et al. (2009) The genome of the blood fluke Schistosoma mansoni. Nature 460(7253), 352-358.

 

2Knobloch J, Kunz W, Grevelding CG. (2006) Herbimycin A suppresses mitotic activity and egg production of female Schistosoma mansoni. Int J Parasitol. 36(12), 1261-1272.


3Blohm AS, Mäder P, Quack T, et al. (2016) Derivatives of biarylalkyl carboxylic acid induce pleiotropic phenotypes in adult Schistosoma mansoni in vitro. Parasitol Res.115(10), 3831–3842.

 

4Mäder P, Blohm AS, Quack T, et al. (2016) Biarylalkyl Carboxylic Acid Derivatives as Novel Antischistosomal Agents. ChemMedChem. 11(13), 1459–1468.

 

5Mäder, P., Rennar, G.A., Ventura, A.M.P., Grevelding, C.G., Schlitzer M. (2018) Chemotherapy for Fighting Schistosomiasis: Past, Present and Future. ChemMedChem. 13(22), 2374-2389.

 

6Peter Ventura, A.M., Haeberlein. S., Lange-Grünweller. K., Grünweller. A., Hartmann. R.K., Grevelding. C.G., Schlitzer. M. (2019) Development of Biarylalkyl Carboxylic Acid Amides with Improved Anti-schistosomal Activity. ChemMedChem. 14(21), 1856-1862.


7Krieg R, Jortzik E, Goetz AA, et al. (2017) Arylmethylamino steroids as antiparasitic agents. Nat Commun. 8,14478.


8Kellershohn, J., Thomas, L., Hahnel, S.R., Grünweller, A., Hartmann, R.K., Hardt, M., Vilcinskas, A., Grevelding, C.G., Haeberlein, S. (2019) Insects in anthelminthics research: Lady beetle-derived harmonine affects survival, reproduction and stem cell proliferation of Schistosoma mansoni. PLoS Negl Trop Dis. 13(3):e0007240.