| Popis: |
Human schistosomiasis is a neglected tropical disease caused bySchistosoma mansoni, S. haematobium,andS. japonicum.Praziquantel (PZQ) is the method of choice for treatment. Due to constant selection pressure, there is an urgent need for new therapies for schistosomiasis. Previous treatment ofS. mansoniincluded the use of oxamniquine (OXA), a drug that is activated by a schistosome sulfotransferase (SULT). Guided by data from X-ray crystallography andSchistosomakilling assays more than 350 OXA derivatives were designed, synthesized, and tested. We were able to identify CIDD-0150610and CIDD-0150303as potent derivativesin vitrothat kill (100%) of all threeSchistosomaspecies at a final concentration of 71.5 µM. We evaluated the efficacy of the best OXA derivates in anin vivomodel after treatment with a single dose of 100 mg/kg by oral gavage. The highest rate of worm burden reduction was achieved by CIDD-150303(81.8%) againstS. mansoni, CIDD-0149830(80.2%) againstS. haematobiumand CIDD-066790(86.7%) againstS. japonicum. We have also evaluated the ability of the derivatives to kill immature stages since PZQ does not kill immature schistosomes. CIDD-0150303demonstrated (100%) killing for all life stages at a final concentration of 143 µMin vitroand effective reduction in worm burdenin vivoagainstS. mansoni. To understand how OXA derivatives fit in the SULT binding pocket, X-ray crystal structures of CIDD-0150303and CIDD-0150610demonstrate that the SULT active site will accommodate further modifications to our most active compounds as we fine tune them to increase favorable pharmacokinetic properties. Treatment with a single dose of 100 mg/kg by oral gavage with co-dose of PZQ + CIDD-0150303 reduced the worm burden of PZQ resistant parasites in an animal model by 90.8%. Therefore, we conclude that CIDD-0150303, CIDD-0149830and CIDD-066790are novel drugs that overcome some of PZQ limitations, and CIDD-0150303can be used with PZQ in combination therapy.Author SummaryHuman schistosomiasis is a neglected tropical disease caused by parasitic worms in the genusSchistosoma. Human schistosomiasis is caused mainly by three major species:S. mansoni, S. haematobium,andS. japonicum.It affects some 229 million people in 78 countries. Currently, there is no effective vaccine against human schistosomiasis. Praziquantel is the method of choice for treatment and evidence for drug resistance has been reported. Our focus is drug discovery for schistosomiasis. Our project team is designing, synthesizing, and testing reengineered derivatives of oxamniquine against the three human species ofSchistosoma. The aim is to develop a new drug for schistosomiasis to overcome developing resistance and improve efficacy. We developed and identified compounds that kill all three humanSchistosomaspecies in addition to a PZQ-resistant strain in animal models. Additionally, animal studies demonstrate that combination treatment of reengineered oxamniquine drugs and praziquantel effectively reduced the infection with a praziquantel resistant strain in infected mice. |
