Praziquantel Affects the Regulatory Myosin Light Chain of Schistosoma mansoni

Abstract

Praziquantel (PZQ) is the drug of choice for schistosomiasis and probably is the only highly effective drug currently available for treating schistosomiasis-infected individuals. The mode of action of PZQ involves increasing the calcium uptake of the parasite, resulting in tegumental damage and death of the parasite. Despite its remarkable function, the target of PZQ has not been identified yet. To begin to understand where PZQ acts, in this study we expressed the cDNA library of Schistosoma mansoni on the surface of T7 bacteriophages and screened this library with labeled PZQ. This procedure identified a clone that strongly bound to PZQ. Subsequent DNA analysis of inserts showed that the clone coded for regulatory myosin light chain protein. The gene was then cloned, and recombinant S. mansoni myosin light chain (SmMLC) was expressed. Immunoblot analysis using antibodies raised to recombinant SmMLC (rSmMLC) showed that SmMLC is abundantly expressed in schistosomula and adult stages compared to the amount in cercarial stages. In vitro analyses also confirmed that PZQ strongly binds to rSmMLC. Further, peptide mapping studies showed that PZQ binds to amino acids 46 to 76 of SmMLC. Immunoprecipitation analysis confirmed that SmMLC is phosphorylated in vivo upon exposure to PZQ. Interestingly, significant levels of anti-SmMLC antibodies were present in vaccinated mice compared to the amount in infected mice, suggesting that SmMLC may be a potential target for protective immunity in schistosomiasis. These findings suggest that PZQ affects SmMLC function, and this may have a role in PZQ action.

Effect of Lactobacillus sporogenes (probiotic) on certain parasitological and molecular aspects in Schistosoma mansoni infected mice

“…Also, Morsy (2009) illustrated that S. mansoni infected mice and treated with PZQ gave reduction of total worm burden, produced marked hepatic shift and improvement of hepatic pathology, reduction in granuloma size and decrease in its number. This may be due to the mode of action of PZQ against S. mansoni which involves increasing the calcium uptake of the parasite, resulting in tegumental damage and death of the parasite as reported by Gnanasekar et al (2009). They suggested that PZQ affected S. mansoni myosin light chain (SmMLC) function, and this may be have a role in PZQ action.…”

An invertebrate smooth muscle with striated muscle myosin filaments

“…Our interest in these muscles was catalyzed by reports that the drug used to treat schistosomiasis (praziquantel) may act on the myosin molecule (15), and that muscle proteins like myosin, paramyosin, and certain regions of actin might be useful targets for the development of an antischistosomal vaccine or chemotherapy (16)(17)(18). We show that the adult form of S. mansoni has exclusively smooth muscles, and yet its thick filaments have the bipolar, helical structure characteristic…”

Efficacy and Safety of Arachidonic Acid for Treatment of Schistosoma mansoni-Infected Children in Menoufiya, Egypt

“…1,3,[5][6][7][8] The side effects are relatively mild, involving essentially headache, dizziness, rashes, nausea, abdominal pain, and diarrhea, symptoms that could be easily explained by the propensity of PZQ to bind to actin. 9,10 Failure of cure after PZQ chemotherapy was consistently associated with high intensity of infection, [5][6][7][8] which required repeated treatments and accelerated the impending threat of schistosome resistance to the drug. 11 Accordingly, use of other schistosomicides alone or combined with PZQ was sought with variable results.…”