Characterisation of enzyms for drug development
This project focuses on the analysis of cytosolic kinases (SmAbl1, SmAbl2, SmTK6)1,2, two aldehyde dehydrogenases (SmALDH1 & 2) and the aldose reductase (SmAR) of Schistosoma mansoni. SmAR and SmALDHs appear to play a role in antioxidative defence, while kinases are involved in differentiation processes, especially in females, and in gonadal development3. The aim of the work is to characterize and validate these enzymes as suitable targets for chemical substances or their derivatives4,5. For this purpose, the selected genes are cloned and expressed in E. coli or other systems (Fig. 1). Activity assays are used to characterize the function of these enzymes in more detail (Fig. 2). Localisations of the transcripts of the corresponding genes are performed by in-situ hybridisation in adult schistosomes, and the functional analysis is carried out by RNA interference. In addition, various already known inhibitors of these enzymes are tested for their efficacy against schistosomula as well as adult schistosomes in vitro or on the expressed enzyme. The enzymes will be crystallized in order to search for further interacting substances after successful elucidation of their structures. This work should provide information about the suitability of a molecule as preferable target, and which of the tested substances may potentially serve as basis for further development into novel active substances against schistosomiasis.
1Beckmann S, Grevelding CG (2010) Imatinib makes a fatal impact on morphology, pairing stability, and survival of adult S. mansoni in vitro. Int J Parasitol. 40, 521-26.
2Beckmann, S., Hahnel, S., Dissous, C., Cailliau, K., Browaeys, E., Grevelding, C.G. (2011) Characterization of the Src/Abl hybrid-kinase SmTK6 of Schistosoma mansoni. J Biol Chem. 286, 42325-42336.
3Grevelding, C.G., Langner, S., Dissous, C. (2018) Kinases: molecular stage directors for schistosome development and differentiation. Trends Parasitol. 34(3), 246-260.
4Dissous C, Grevelding CG (2011) Piggy-backing cancer drugs for schistosomiasis treatment, a tangible perspective? Trends Parasitol. 27, 59-66.
5Gelmedin, V., Dissous, C., Grevelding, C.G. (2015) Re-positioning protein kinase inhibitors against schistosomiasis. Fut Med Chem. 7(6), 737-752.