Small change, big difference: A novel praziquantel derivative P96 with multistage antischistosomal activity for chemotherapy of schistosomiasis japonica

BackgroundPraziquantel (PZQ) has been the first line antischistosomal drug for all species of Schistosoma, and the only available drug for schistosomiasis japonica, without any alternative drugs since the 1980s. However, PZQ cannot prevent reinfection, and cannot cure schistosomiasis thoroughly because of its poor activity against juvenile schistosomes. In addition, reliance on a single drug is extremely dangerous, the development and spread of resistance to PZQ is becoming a great concern. Therefore, development of novel drug candidates for treatment and control of schistosomiasis is urgently needed. Methodologys/Principal findingsA novel PZQ derivative P96 was synthesized with the substitution of cyclohexyl by cyclopentyl. We investigated the in vitro and in vivo activities of our drug candidate P96 against different developmental stages of S. japonicum. Parasitological studies and scanning electron microscopy were used to study the primary action characteristics of P96 in vitro. Both mouse and rabbit models were employed to evaluate schistosomicidal efficacy of P96 in vivo. Besides calculation of worm reduction rate and egg reduction rate, quantitative real-time PCR was used to evaluate the in vivo antischistosomal activity of P96 at molecular level. In vitro, after 24h exposure, P96 demonstrated the highest activities against both juvenile and adult worm of S. japonicum in comparison to PZQ. The antischistosomal efficacy was concentration-dependent, with P96 at 50M demonstrating the most evident schistosomicidal effect. Scanning electron microscopy demonstrated that P96 caused more severe damages to schistosomula and adult worm tegument compared to PZQ. In vivo, our results showed that P96 was effective against S. japonicum at all developmental stages. Notably, its efficacy against young stage worms was significantly improved compared to PZQ. Moreover, P96 retained the high activity comparable to PZQ against the adult worm of S. japonicum. ConclusionsP96 is a promising drug candidate for chemotherapy of schistosomiasis japonica, which has broad spectrum of action against various developmental stage, potentially addressing the deficiency of PZQ. It might be promoted as a drug candidate for use either alone or in combination with PZQ for the treatment of schistosomiasis. Author SummarySchistosomiasis is one of the neglected tropical diseases caused by infection of Schistosoma spp. Currently, in the absence of effective vaccines for schistosomiasis, PZQ is the first line drug chosen for the treatment and control of schistosomiasis in most developing countries. However, after long-term and large-scale administration of PZQ, drug-resistance has been a great concern. Therefore, there is a need for new therapies. In this study, with the aim of preventing the formation of less effective metabolite 4-trans-cyclohexanol, a novel PZQ derivative, P96, is synthesized with the cyclohexyl group substituted by cyclopentyl group. It is this small modification that gives us a big surprise. In vitro, all the biological assessments, including viability reduction rate and morphological properties by scanning electron microscopy, demonstrate that P96 has superior anti-schistosomula activity compared to PZQ, and retains similar or even higher anti-adult S. japonicum activity to PZQ. The antischistosomal effect of P96 is dose-dependent. In vivo, P96 displays high efficacy against all developmental stages of S. japonicum, with significantly improved efficacy against young stage worms compared to PZQ. Furthermore, the quantitative detection results of specific circulatory SjR2 DNA prove that P96 has similar activity to PZQ against adult schistosome at molecular level in rabbit sera with infection of schistosomiasis. In conclusion, the novel PZQ derivative, P96 is a promising drug candidate for chemotherapy of schistosomiasis, potentially addressing the deficiency of PZQ, and might be promoted for use either alone or in combination with PZQ for treatment and control of schistosomiasis.