Effect of Praziquantel on Schistosoma mekongi Proteome and Phosphoproteome

Abstract

Schistosoma mekongi causes schistosomiasis in southeast Asia, against which praziquantel (PZQ) is the only treatment option. PZQ resistance has been reported, thus increasing the requirement to understand mechanism of PZQ. Herein, this study aimed to assess differences in proteome and phosphoproteome of S. mekongi after PZQ treatment for elucidating its action. Furthermore, key kinases related to PZQ effects were predicted to identify alternative targets for novel drug development. Proteomes of S. mekongi were profiled after PZQ treatment at half maximal inhibitory concentration and compared with untreated worms. A total of 144 proteins were differentially expressed after treatment. In parallel, immunohistochemistry indicated a reduction of phosphorylation, with 43 phosphoproteins showing reduced phosphorylation, as identified by phosphoproteomic approach. Pathway analysis of mass spectrometric data showed that calcium homeostasis, worm antigen, and oxidative stress pathways were influenced by PZQ treatment. Interestingly, two novel mechanisms related to protein folding and proteolysis through endoplasmic reticulum-associated degradation pathways were indicated as a parasiticidal mechanism of PZQ. According to kinase–substrate predictions with bioinformatic tools, Src kinase was highlighted as the major kinase related to the alteration of phosphorylation by PZQ. Interfering with these pathways or applying Src kinase inhibitors could be alternative approaches for further antischistosomal drug development.

Preclinical Evaluations of Modified Rice Hydrogel for Topical Ophthalmic Drug Delivery of Praziquantel on Avian Philophalmiasis

“…In addition, the concentration of 10 µg/mL PZQ (Chi squared test, p = 0.003) and exposure time for 24 h (log-rank test, p = 0.0004) is sufficient to kill parasites, when statistically compared to negative control group. These findings are in agreement with previous studies in the parasiticidal activity of PZQ against trematode, in which the 40 μg/mL concentration of PZQ reduced viability of the Schistosoma mekongi by approximately the half maximal inhibitory concentration (IC50) [ 28 ]. The parasiticidal activity of prazquantel against cretodes, including Hymenolepis nana (1 µg/mL) for 5 min and Diphyllobothrium latum (0.1 µg/mL) for 4 h, was previously reported [ 29 , 30 ].…”

Metabolomics reveal alterations in arachidonic acid metabolism in Schistosoma mekongi after exposure to praziquantel

“…While, the controls were noticed the body-bend amplitude during locomotion. We found that the three concentrations reduced the viability of parasites by 0%, 46.7%, and 100%, respectively [ 24 ]. Metabolites from these three conditions were extracted and compared with those from the control (0 μg/mL PZQ).…”

“…Thereafter, PZQ (Tokyo Chemical Industry, Tokyo, Japan) was dissolved in dimethyl sulfoxide and diluted to a final concentration of 0 (control), 20, 40 (IC 50 ), and 100 μg/mL with RPMI medium. The inhibitory concentration associated with 50% effect (IC 50 ), used in this study, was determined as described in our previous publication [ 24 ]. Each concentration of PZQ was added to 10 pairs of S .…”

Protein Kinases: Potential Drug Targets Against Schistosoma japonicum

“…The importance of PKs has also been noted in other species of schistosomes, one example being Schistosoma mekongi ( S. mekongi ). A study explored the effect of PZQ on S. mekongi proteome and phosphoproteome, in which it was found that proto-oncogene tyrosine-protein kinase Src was mainly associated with the alteration of phosphorylation for PZQ response by kinase–substrate predictions ( Chienwichai et al., 2020 ). Therefore, applying Src kinase inhibitors could be a novel approach to treat Mekong schistosomiasis.…”