Department of Parasitology, School of Basic Medical Sciences, Suzhou Medical College of Soochow University, Suzhou City, P. R. China.
MOE Key Laboratory of Geriatric Diseases and Immunology, Suzhou Key Laboratory of Pathogen Bioscience and Anti-infective Medicine, Suzhou Medical College, Soochow University, Suzhou City, P. R. China.
PLoS Negl Trop Dis. 2024 Aug 19;18(8):e0012428. doi: 10.1371/journal.pntd.0012428. eCollection 2024 Aug.
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.
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.
血吸虫病是一种相对被忽视的寄生虫病，影响着全球超过 2.5 亿人，其控制策略主要依赖于使用唯一可用的药物——吡喹酮（PZQ）进行大规模治疗。这种方法是不可持续的，因此开发新型药物候选物来治疗和控制血吸虫病是当务之急。
方法/主要发现：在我们之前的研究中，我们发现 DW-3-15，一种 PZQ 衍生物，可以显著下调日本血吸虫（SjHAT）的组蛋白乙酰转移酶的表达。在这项研究中，我们筛选了几种市售的 HAT 抑制剂，A485、C646 和姜黄素，以验证它们对日本血吸虫幼体和成虫的抗血吸虫活性。寄生虫学研究和扫描电子显微镜用于研究 HAT 抑制剂在体外的主要作用特征。定量实时 PCR 用于检测不同 HAT 抑制剂处理后 SjHAT 的 mRNA 水平。我们的结果表明，姜黄素是最有效的抑制剂，对日本血吸虫的幼体和成虫都有效果，其杀血吸虫效果呈时间和剂量依赖性。然而，A485 和 C646 的抗血吸虫活性有限。扫描电子显微镜显示，与 DW-3-15 相比，姜黄素引起雄性成虫相似的表皮变化。此外，姜黄素和 DW-3-15 均显著降低 SjHAT 的 mRNA 水平，并且姜黄素剂量依赖性地降低雌性、雄性和幼体蠕虫中的 SjHAT 表达水平。
在三种市售的 HAT 中，姜黄素对血吸虫最有效。姜黄素和我们的专利化合物 DW-3-15 均显著下调 SjHAT 的表达，表明 SjHAT 可能是开发新型抗血吸虫药物候选物的潜在治疗靶点。
