| Abstrakt: |
Background: Schistosomiasis is a relatively neglected parasitic disease that afflicts more than 250 million people worldwide, for which the control strategy relies mainly on mass treatment with the only available drug, praziquantel (PZQ). This approach is not sustainable and is a priority for developing novel drug candidates for the treatment and control of schistosomiasis. Methodologys/Principal findings: In our previous study, we found that DW-3-15, a kind of PZQ derivative, could significantly downregulate the expression of the histone acetyltransferase of Schistosoma japonicum (SjHAT). In this study, several commercially available HAT inhibitors, A485, C646 and curcumin were screened in vitro to verify their antischistosomal activities against S. japonicum juveniles and adults. Parasitological studies and scanning electron microscopy were used to study the primary action characteristics of HAT inhibitors in vitro. Quantitative real-time PCR was employed to detect the mRNA level of SjHAT after treatment with different HAT inhibitors. Our results demonstrated that curcumin was the most effective inhibitor against both juveniles and adults of S. japonicum, and its schistosomicidal effects were time- and dose dependent. However, A485 and C646 had limited antischistosomal activity. Scanning electron microscopy demonstrated that in comparison with DW-3-15, curcumin caused similar tegumental changes in male adult worms. Furthermore, both curcumin and DW-3-15 significantly decreased the SjHAT mRNA level, and curcumin dose-dependently reduced the SjHAT expression level in female, male and juvenile worms. Conclusions: Among the three commercially available HATs, curcumin was the most potent against schistosomes. Both curcumin and our patent compound DW-3-15 markedly downregulated the expression of SjHAT, indicating that SjHAT may be a potential therapeutic target for developing novel antischistosomal drug candidates. Author summary: Schistosomiasis is a zoonotic parasitic disease caused by Schistosoma spp. infection. Due to the lack of effective vaccines for schistosomiasis, PZQ is the only available drug chosen for the treatment and control of schistosomiasis in most developing countries. Drug resistance due to long-term, large-scale and single-agent use has been a great concern. Therefore, there is an urgent need for new therapies. In our previous study, we developed the patented compound DW-3-15 (patent no. ZL201110142538.2), which has significant and stable antiparasitic activity, and can significantly decrease the expression of S. japonicum histone acetyltransferase (SjHAT). As we known, HATs are a class of epigenetic enzymes that are crucial for chromatin restructuring and transcriptional regulation in mammals and in parasitic development, and are thus promising targets for antischistosomal therapeutic development. In this study, we assessed three commercial HATs, including two selective p300/CBP inhibitors A485 and C646, and one natural compound, curcumin. Our results demonstrated that curcumin had the most potent worm-killing efficacy against S. japonicum juveniles and adults. In contrast, A485 and C646 displayed no effects on adult worms or mild effects on juveniles. Moreover, curcumin caused severe damage to the tegument of male worms, and the damage was similar to that of DW-3-15. Coincidentally, both curcumin and DW-3-15 significantly downregulated the expression of SjHAT, indicating that SjHAT might be an effective target for the development of novel therapeutic drugs. The screening and identification of selective HAT inhibitors may be a promising strategy for developing novel antischistosomal agents. [ABSTRACT FROM AUTHOR] |
