Deubiquitinating enzymes as possible drug targets for schistosomiasis.

Affiliation

Barban do Patrocínio A(1), Cabral FJ(2), de Paiva TH(3), Magalhães LG(4), Paula LAL(5), Brigato OM(6), Guerra-Sá R(3), Rodrigues V(7).
Author information:
(1)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.
(2)Institute of Biology, University State of Campinas
(Department of Animal Biology). Rua Monteiro Lobato, 255. Campinas
(São Paulo) Brazil; CEP 13083-862. Electronic address: [Email]
(3)Institute of Exact and Biological Sciences, Federal University of Ouro Preto, Campus Universitário Morro do Cruzeiro- Bauxita. Ouro Preto
(Minas Gerais), Brazil; CEP 35400-000.
(4)Research Group on Natural Products
(Center for Research in Sciences and Technology), University of Franca. Av. Dr. Armando de Sáles Oliveira, 201 - Parque Universitário, Franca
(São Paulo), Brazil; CEP 14404-600. Electronic address: [Email]
(5)Research Group on Natural Products
(Center for Research in Sciences and Technology), University of Franca. Av. Dr. Armando de Sáles Oliveira, 201 - Parque Universitário, Franca
(São Paulo), Brazil; CEP 14404-600.
(6)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. Electronic address: [Email]
(7)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. Electronic address: [Email]

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.