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Protein kinases, potential targets of novel treatment strategies

Protein kinases, potential targets of novel treatment strategies


For decades, Praziquantel (PZQ) is the drug of choice for schistosomiasis treatment and a vaccine is not available. With respect to first evidence of the possibility of upcoming PZQ resistance1,2, great efforts are undertaken worldwide to find new chemotherapeutic options for treatment.

Protein kinases (PKs) are essential members of signal transduction cascades that mediate molecular communication processes within and between cells. In this respect PKs are indispensable to life. Because aberrant PK functions take distinctive roles in human diseases they represent targets in chemotherapies. Results of research activities from our lab have shown that conserved PKs exist in Schistosoma mansoni and perform a broad spectrum of activities contributing among others to reproduction processes and the maintenance of tissue integrity3,4. Exploiting the similarity of PKs of humans and schistosomes (as well as other parasites), PK inhibitors designed for the treatment of human diseases (such as Imatinib, a cancer drug; see image) may serve as lead compounds for new drugs against schistosomiasis (and further infectious diseases caused by parasites). First research results in this research area have confirmed that this approach is promising for fighting schistosomes4-8 but also other parasites8-12. A case report of a 29-years old women infected with fliariae showed a therapeutic effect of Imatinib15

 

Kontrollpärchen unbehandelt_Imatinib1_Figur 1.jpgPärchen behandelt_Imatinib2_Figur 2.jpg

Schistosome couples before (left) und following treatment with Imatinib (right) in vitro. Without treatment adult schistosomes suck with their ventral suckers to the Petri dish, and they perform wave-like movements. Pairing is stable, and the female resides within the ventral grove of their male partner (see movie 1). Following Imatinib treatment the couples separate. The worms do not suck anymore, they lie on the side, get stiff, and die finally (see movie 2). Bulge-like swelling are frequently observed in the gonads (see star) and the gastrodermis4.    

 

Movie 1: Untreated schistosome couple4

 

Movie 2: Schistosome couple treated with Imatinib4

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

1Cioli D, Pica-Mattoccia L, Basso A, Guidi A. (2014) Schistosomiasis control: praziquantel forever? Mol Biochem Parasitol. 195(1):23-9.

 

2Chai JY. (2013) Praziquantel treatment in trematode and cestode infections: an update.

Infect Chemother. 45(1):32-43.

 

3Beckmann S, Quack T, Burmeister C, Buro C, Long T, Dissous C, Grevelding CG (2010) Schistosoma mansoni: Signal transduction processes during the development of the reproductive organs. Parasitology 137:497-520.

 

4Beckmann 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.

 

5Dissous C, Grevelding CG (2011) Piggy-Backing cancer drugs for schistosomiasis treatment, a tangible perspective? Trends Parasitol. 27, 59-66.

 

6Morel M, Vanderstraete M, Hahnel S, Grevelding CG, Dissous C (2014) Receptor tyrosine kinases and schistosome reproduction: new targets for chemotherapy. Front Genet. 5:238.

 

7Gelmedin V, Dissous C, Grevelding CG (2015) Re-positioning protein kinase inhibitors against schistosomiasis. Future Med Chem. 7(6):737-52.

 

8Li, X., Haeberlein, S., Zhao, L., Mughal, M.N., Zhu, T., Liu, L., Fang, R., Zhou, Y., Zhao, J., Grevelding, C.G., Hu, M. (2019) The ABL kinase inhibitor imatinib causes phenotypic changes and lethality in adult Schistosoma japonicum. Parasitol Res. 118(3):881-890

 

9Doerig C, Grevelding CG (2015) Importance of kinases in Plasmodium and Schistosoma. Biochem Biophys Acta 1854: 1637–43.

 

10Pathak V, Colah R, Ghosh K. (2015) Tyrosine kinase inhibitors: New class of antimalarials on the horizon? Blood Cells Mol Dis. 55(2):119-26

 

11Geary TG, Mackenzie CD. (2015) Adding "filaricide" to the Gleevec portfolio. J Infect Dis. 212(5):677-80.

 

12O'Connell EM, Bennuru S, Steel C, Dolan MA, Nutman TB. (2015) Targeting filarial Abl-like kinases: orally available, food and drug administration-approved tyrosine kinase inhibitors are microfilaricidal and macrofilaricidal. J Infect Dis. 212(5):684-93.

 

13Hemer S, Brehm K. (2012) In vitro efficacy of the anticancer drug imatinib on Echinococcus multilocularis larvae. Int J Antimicrob Agents. 40(5):458-62.

 

14O'Connell, E.M., Kamenyeva, O., Lustigman, S., Bell, A., Nutman, T.B. (2017) Defining the target and the effect of imatinib on the filarial c-Abl homologue. PLoS Negl Trop Dis. 11(7):e0005690.

 

15O'Connell, E.M., Nutman, T.B. (2017) Reduction of Loa loa Microfilaremia with Imatinib - A Case Report. N Engl J Med. 377(21):2095-2096.