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

摘要: Background Chemotherapy of schistosomiasis relies on a single drug, Praziquantel (PZQ) and mass-use this compound has led to emergence resistant strains Schistosoma mansoni, therefore pointing out the necessity find alternative drugs. Through their essential functions in development metabolism, receptor tyrosine kinases (RTK) could represent valuable drug targets for novel anti-schistosome chemotherapies. Taking advantage similarity between catalytic domains S. mansoni insulin receptors (SmIR1 SmIR2) Venus Kinase Receptors (SmVKR1 SmVKR2), we studied possibility fight schistosomes by targeting simultaneously four with drug. Methodology/Principal Findings Several commercial RTK inhibitors were tested potential inhibit kinase activities SmIR1, SmIR2, SmVKR1 SmVKR2 intracellular (ICD) expressed Xenopus oocytes. We measured inhibitory effect chemicals meiosis resumption induced active ICD schistosome The IR inhibitor, tyrphostin AG1024, was most potent towards SmIR SmVKR kinases. In vitro studies then allowed us show that AG1024 affected viability both schistosomula adult worms mansoni. At micromolar doses, apoptosis caused death dose-dependent manner. worms, provoked alterations reproductive organs, as observed confocal laser scanner microscopy. With 5 µM parasites no more feeding laying eggs, they died within 48 h 10 µM. Conclusion/Significance IRs VKRs are key biological processes including glucose uptake, metabolism reproduction. Our results demonstrate inhibiting function these chemical at low concentrations, leads worms. Thus, represents hit further design anti-kinase drugs applicable chemotherapy.