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Dual Targeting of Insulin and Venus Kinase Receptors of Schistosoma mansoni for Novel Anti-schistosome Therapy

Abstract : Background: Chemotherapy of schistosomiasis relies on a single drug, Praziquantel (PZQ) and mass-use of this compoundhas led to emergence of resistant strains ofSchistosoma mansoni, therefore pointing out the necessity to find alternativedrugs. Through their essential functions in development and metabolism, receptor tyrosine kinases (RTK) could representvaluable drug targets for novel anti-schistosome chemotherapies. Taking advantage of the similarity between the catalyticdomains ofS. mansoniinsulin receptors (SmIR1 and SmIR2) and Venus Kinase Receptors (SmVKR1 and SmVKR2), we studiedthe possibility to fight schistosomes by targeting simultaneously the four receptors with a single drug. Methodology/Principal Findings: Several commercial RTK inhibitors were tested for their potential to inhibit the kinaseactivities of SmIR1, SmIR2, SmVKR1 and SmVKR2 intracellular domains (ICD) expressed inXenopusoocytes. We measured theinhibitory effect of chemicals on meiosis resumption induced by the active ICD of the schistosome kinases in oocytes. The IRinhibitor, tyrphostin AG1024, was the most potent inhibitory compound towards SmIR and SmVKR kinases.In vitrostudiesthen allowed us to show that AG1024 affected the viability of both schistosomula and adult worms ofS. mansoni.Atmicromolar doses, AG1024 induced apoptosis and caused schistosomula death in a dose-dependent manner. In adultworms, AG1024 provoked alterations of reproductive organs, as observed by confocal laser scanner microscopy. With 5mMAG1024, parasites were no more feeding and laying eggs, and they died within 48 h with 10mM. Conclusion/Significance: IRs and VKRs are essential inS. mansonifor key biological processes including glucose uptake,metabolism and reproduction. Our results demonstrate that inhibiting the kinase potential and function of these receptorsby a single chemical compound AG1024 at low concentrations, leads to death of schistosomula and adult worms. Thus,AG1024 represents a valuable hit compound for further design of anti-kinase drugs applicable to anti-schistosomechemotherapy.
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https://hal.univ-lille.fr/hal-03200290
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Soumis le : vendredi 16 avril 2021 - 13:46:49
Dernière modification le : mardi 19 octobre 2021 - 23:56:32
Archivage à long terme le : : samedi 17 juillet 2021 - 18:41:58

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Mathieu Vanderstraete, Nadège Gouignard, Katia Cailliau-Maggio, Marion Morel, Julien Lancelot, et al.. Dual Targeting of Insulin and Venus Kinase Receptors of Schistosoma mansoni for Novel Anti-schistosome Therapy. PLoS Neglected Tropical Diseases, Public Library of Science, 2013, 7 (5), pp.e2226. ⟨10.1371/journal.pntd.0002226⟩. ⟨hal-03200290⟩

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