Medicine Faculty of Ribeirão Preto, University of São Paulo (Department of Biochemistry and Immunology). Avenue Bandeirantes, 3900. Ribeirão Preto (São Paulo), Brazil; CEP 14049-900.
Institute of Biology, University State of Campinas (Department of Animal Biology). Rua Monteiro Lobato, 255. Campinas (São Paulo) Brazil; CEP 13083-862.
Acta Trop. 2021 May;217:105856. doi: 10.1016/j.actatropica.2021.105856. Epub 2021 Feb 9.
Deubiquitinating enzymes (DUBs) are conserved in Schistosoma mansoni and may be linked to the 26S proteasome. Previous results from our group showed that b-AP15, an inhibitor of the 26S proteasome DUBs UCHL5 and USP14 induced structural and gene expression changes in mature S. mansoni pairs. This work suggests the use of the nonselective DUB inhibitor PR-619 to verify whether these enzymes are potential target proteins for new drug development. Our approach is based on previous studies with DUB inhibitors in mammalian cells that have shown that these enzymes are associated with apoptosis, autophagy and the transforming growth factor beta (TGF-β) signaling pathway. PR-619 inhibited oviposition in parasite pairs in vitro, leading to mitochondrial changes, autophagic body formation, and changes in expression of SmSmad2 and SmUSP9x, which are genes linked to the TGF-β pathway that are responsible for parasite oviposition and SmUCHL5 and SmRpn11 DUB maintenance. Taken together, these results indicate that DUBs may be used as targets for the development of new drugs against schistosomiasis.
去泛素化酶（DUBs）在曼氏血吸虫中保守，可能与 26S 蛋白酶体有关。我们小组之前的研究结果表明，26S 蛋白酶体 DUBsUCHL5 和 USP14 的抑制剂 b-AP15 诱导成熟的曼氏血吸虫对诱导结构和基因表达变化。这项工作表明可以使用非选择性 DUB 抑制剂 PR-619 来验证这些酶是否是新药物开发的潜在靶蛋白。我们的方法基于以前在哺乳动物细胞中进行的 DUB 抑制剂研究，这些研究表明这些酶与细胞凋亡、自噬和转化生长因子-β（TGF-β）信号通路有关。PR-619 在体外抑制寄生虫对的产卵，导致线粒体变化、自噬体形成以及 SmSmad2 和 SmUSP9x 表达的变化，这些基因与 TGF-β 途径有关，负责寄生虫产卵和 SmUCHL5 和 SmRpn11 DUB 的维持。总之，这些结果表明 DUBs 可能被用作开发治疗血吸虫病新药的靶标。
