1. Deubiquitinating enzymes as possible drug targets for schistosomiasis.
- Author
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Barban do Patrocínio A, Cabral FJ, de Paiva TH, Magalhães LG, Paula LAL, Brigato OM, Guerra-Sá R, and Rodrigues V
- Subjects
- Animals, Apoptosis drug effects, Autophagy drug effects, Drug Discovery, Female, Gene Expression Regulation, Life Cycle Stages drug effects, Male, Mice, Mice, Inbred BALB C, Mitochondria drug effects, Mitochondria ultrastructure, Movement drug effects, Oviposition drug effects, Proteasome Endopeptidase Complex metabolism, Real-Time Polymerase Chain Reaction, Schistosoma mansoni ultrastructure, Signal Transduction drug effects, Transforming Growth Factor beta metabolism, Aminopyridines pharmacology, Deubiquitinating Enzymes antagonists & inhibitors, Schistosoma mansoni drug effects, Schistosomiasis drug therapy, Thiocyanates pharmacology
- Abstract
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., (Copyright © 2021. Published by Elsevier B.V.)
- Published
- 2021
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