Compound library screening identified Akt/PKB kinase pathway inhibitors as potential key molecules for the development of new chemotherapeutics against schistosomiasis

International Journal for Parasitology: Drugs and Drug Resistance

Julien Lancelot¹  Colette Dissous¹  Marion Morel¹  Mathieu Vanderstraete¹  Arlette Lescuyer²  Katia Cailliau² 

[1] CIIL – Center of Infection and Immunity of Lille, Université Lille Nord de France, Inserm U1019, CNRS-UMR 8204, Institut Pasteur de Lille, 59019 Lille Cedex, France;Laboratoire de Régulation des Signaux de Division, Université Lille 1 Sciences et Technology, EA 4479, IFR 147, 59655 Villeneuve d’Ascq Cedex, France;

关键词: Protein kinase;    Inhibitor;    Protein kinase B (PKB);    Akt;    Schistosoma mansoni;    Chemotherapy;   

DOI  :  10.1016/j.ijpddr.2014.09.004

来源: DOAJ

【 摘 要 】

Protein kinases (PKs) are one of the largest protein families in most eukaryotic organisms. These enzymes are involved in the control of cell proliferation, differentiation and metabolism and a large number of the anticancer drugs currently used are directed against PKs. The structure and function of PKs are well conserved throughout evolution. In schistosome parasites, PKs were shown to be involved in essential functions at every stage of the parasite life cycle, making these enzymes promising anti-parasite drug targets. In this study, we tested a panel of commercial inhibitors for various PKs and analyzed their effects on pairing and egg production by schistosomes as well as their toxicity towards schistosomula larvae. Results obtained confirmed the deleterious effect of PK targeting on Schistosoma mansoni physiology and the important function of different tyrosine and serine/threonine kinases in the biology and reproduction of this parasite. They also indicated for the first time that the Protein kinase B (also called Akt) which is a major downstream target of many receptor tyrosine kinases and a central player at the crossroads of signal transduction pathways activated in response to growth factors and insulin, can constitute a novel target for anti-schistosome chemotherapy. Structural and functional studies have shown that SmAkt is a conserved kinase and that its activity can be inhibited by commercially available Akt inhibitors. In treated adult worms, Akt/PKB kinase pathway inhibitors induced profound alterations in pairing and egg laying and they also greatly affected the viability of schistosomula larvae.

【 授权许可】

Unknown