In vitro and in vivo activities of DW-3-15, a commercial praziquantel derivative, against Schistosoma japonicum

Abstract

Background Schistosomiasis is a debilitating neglected tropical disease that affects approximately 190 million people around the world. Praziquantel (PZQ) is the only drug available for use against all Schistosoma species. Although PZQ has a high efficacy, recognized concerns have prompted the development of new, alternative drugs for repeated use in endemic areas where PZQ efficacy against strains of Schistosoma is reduced. A hybrid drug containing different pharmacophores within a single molecule is a promising strategy. Our earlier in vivo studies showed the significant antiparasitic activity of a praziquantel derivative, DW-3-15, against Schistosoma japonicum . In the present study, DW-3-15 was synthesized in large amounts by a pharmaceutical company and its schistosomicidal efficacy and stability were further confirmed. Parameters such as parasite viability, pairing and oviposition were evaluated in vitro . An in vivo study was conducted to assess the effect of commercial DW-3-15 on worm burden, egg production and diameter of granulomas. Additionally, to gain insight into the mechanism of action for DW-3-15, morphological changes in the tegument of S. japonicum were also examined. Results The in vitro study showed the antiparasitic activity of DW-3-15 against S. japonicum , with significant reductions in viability of adult and juvenile worms, worm pairings and egg output. Compared to PZQ, DW-3-15 induced similar ultrastructural changes and evident destruction of the tegument surface in male worms. In vivo , the oral administration of DW-3-15 at a dose of 400 mg/kg per day for five consecutive days in mice significantly reduced the total worm burden and number of eggs in the liver. Histological analysis of the livers showed a marked reduction in the average diameter of the egg granuloma. Conclusions Our findings suggest that DW-3-15, a PZQ derivative with the prospect of commercial production, can be developed as a potential promising schistosomicide. Electronic supplementary material The online version of this article (10.1186/s13071-019-3442-7) contains supplementary material, which is available to authorized users.

Inhibition of the NAD salvage pathway in schistosomes impairs metabolism, reproduction, and parasite survival

“…to the primary licensed schistosomiasis treatment, praziquantel, which kills all species of adult schistosomes but does not affect the viability of immature schistosomula either in vitro or in vivo [11][12][13][14][15]. Our data therefore suggest that a new class of drugs that specifically targets the NAD salvage pathway in schistosomes could potentially be used to kill both adult and immature worms.…”

“…Humans infected with schistosomes are commonly treated with praziquantel which, while effective against all three major species of schistosome [8], exhibits minimal efficacy against the immature schistosomula [11][12][13][14][15]. Given the importance of NAD redox reactions in many metabolic pathways and the apparent lack of genes encoding de novo NAD pathway enzymes in S. mansoni, we hypothesized that blocking the NAD salvage pathway in immature S. mansoni would also affect NAD homeostasis and the metabolic and biologic properties of the immature parasites.…”

“…Currently, praziquantel is the predominant drug used to treat this infection. Although praziquantel is inexpensive and has activity against all adult schistosome species [8], it is minimally effective against immature schistosomes [11][12][13][14][15] and cannot be used prophylactically to prevent the establishment of disease in high-risk individuals. Furthermore, some schistosome species exhibit praziquantel resistance in the lab and in the field [16].…”

Synergistic effect of combination chemotherapy with praziquantel and DW-3-15 for Schistosoma japonicum in vitro and in vivo

“…Notably, compared with PZQ, DW-3-15 showed improved antiparasitic activity against juvenile worms, while still demonstrating promising schistosomicidal efficacy against adults [ 13 ]. In addition, the commercial DW-3-15 synthesized by a pharmaceutical company showed reproducible antischistosomal activity, highlighting its activity and stability [ 14 ]. Although DW-3-15 was highly effective against schistosomes, with worm reduction rates ranging from 63.4 to 85.7%, it failed to clear all the worms from S. japonicum -infected mice [ 13 , 14 ].…”

“…In addition, the commercial DW-3-15 synthesized by a pharmaceutical company showed reproducible antischistosomal activity, highlighting its activity and stability [ 14 ]. Although DW-3-15 was highly effective against schistosomes, with worm reduction rates ranging from 63.4 to 85.7%, it failed to clear all the worms from S. japonicum -infected mice [ 13 , 14 ]. Similar observations were reported for PZQ, which failed to achieve 100% worm reduction when used alone [ 15 ].…”