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Effect of ozonide OZ418 against Schistosoma japonicum harbored in mice
Jian Xue1, Xiaofang Wang, Yuxiang Dong
1National Institute of Parasitic Diseases, Chinese Center for Disease Control and Prevention, Key Laboratory of Parasite and Vector Biology, MOH, WHO Collaborating Centre for Malaria, Schistosomiasis, and Filariasis, Shanghai, 200025, People's Republic of China, xuejian74@allyun.com.
Abstract:
The in vitro and in vivo efficacies of ozonide carboxylic acid OZ418 against Schistosoma japonicum were investigated. For in vitro experiments, juvenile (14-day-old) and adult schistosomes were collected from mice infected with 80-100 S. japonicum cercariae for 14 and 35 days post-infection and the worms were maintained in Roswell Park Memorial Institute (RPMI) 1640 supplemented by 10% calf serum. Against 35-day-old adult S. japonicum, OZ418 resulted in weakened worm motor activity, injury to the worm body, emergence of vacuoles along the worm surface, and death. A similar outcome was seen in 14-day-old juvenile S. japonicum exposed to OZ418. Ineffective concentrations (1, 5, and 10 μg/mL) of OZ418 also interacted with hemin to significantly increase the killing effect against adult schistosomes. The LC50 value of OZ418 against juvenile (14-day-old) and adult schistosomes were identical--16.2 μg/mL, whereas the corresponding LC95 values were 30.7 and 22.7 μg/mL, respectively. Treatment of adult and juvenile (14-day-old) S. japonicum-infected mice with single 200-400-mg/kg oral doses of OZ418 produced total worm burden reductions of 68.5-84.1 and 37.5-50.9%, respectively. Further study showed that in mice infected with various stages of schistosomes and treated with a single oral OZ418 400 mg/kg, poor efficacy was seen in the 3-h-old juvenile worm group, while 14-day-old and 21-day-old juvenile worm groups exhibited less efficacy with total worm burden reductions of 42.6-52.4%. On the other hand, similar and higher total worm burden reductions (64.2-76.0%) were seen in the 7-day-old juvenile worm group and 28-day-old as well as 35-day-old adult worm groups. Furthermore, the mean worm burden reductions of the 7-day-old juvenile worm group and 35-day-old adult worm group were statistically significantly higher than that of the 14-day-old or 21-day-old juvenile worm group (P < 0.01 or <0.05). These data suggest that OZ418 has promising efficacy against 7-day-old juvenile and adult S. japonicum.
Insights
Ozonide carboxylic acid OZ418 shows promising efficacy against Schistosoma japonicum, particularly in 7-day-old juvenile and adult worms. This novel compound demonstrates significant potential for treating schistosomiasis in vivo.
Area of Science:
- Parasitology
- Medicinal Chemistry
- Drug Discovery
Background:
- Schistosomiasis japonica remains a significant human health concern, necessitating novel therapeutic agents.
- Current treatments face challenges including resistance and side effects, driving the search for new drugs.
- Ozonide carboxylic acid OZ418 is a potential candidate for antiparasitic therapy.
Purpose of the Study:
- To investigate the in vitro and in vivo efficacy of ozonide carboxylic acid OZ418 against Schistosoma japonicum.
- To determine the optimal stage of Schistosoma japonicum for OZ418 treatment.
- To evaluate the synergistic effect of OZ418 with hemin.
Main Methods:
- In vitro assays using juvenile (14-day-old) and adult S. japonicum worms.
- In vivo studies in mice infected with various developmental stages of S. japonicum.
- Administration of single oral doses of OZ418 (200-400 mg/kg).
- Assessment of worm motor activity, morphological damage, and worm burden reduction.
Main Results:
- OZ418 induced mortality, motor impairment, and physical damage in both juvenile and adult S. japonicum in vitro.
- The LC50 of OZ418 was 16.2 μg/mL for both juvenile and adult worms.
- In vivo, OZ418 demonstrated significant worm burden reduction, with higher efficacy against 7-day-old juvenile and adult worms (64.2-76.0%) compared to 14- and 21-day-old juvenile worms (42.6-52.4%).
- Hemin enhanced the killing effect of ineffective OZ418 concentrations against adult schistosomes.
Conclusions:
- OZ418 exhibits promising efficacy against Schistosoma japonicum, particularly in 7-day-old juvenile and adult stages.
- The compound shows potential as a novel therapeutic agent for schistosomiasis.
- Further research into OZ418's mechanism of action and safety profile is warranted.
