Deubiquitinating enzymes as possible drug targets for schistosomiasis

Author(s)

do Patrocinio, Andressa Barban ^[1] ; Cabral, Fernanda Janku ^[2] ; de Paiva, Thales Henrique ^[3] ; Magalhaes, Lizandra Guidi ^[4] ; de Lima Paula, Lucas Antonio ^[4] ; Brigato, Olinda Mara ^[1] ; Guerra-Sa, Renata ^[3] ; Rodrigues, Vanderlei ^[1]

Affiliation

^[1] Univ Sao Paulo, Med Fac Ribeirao Preto, Dept Biochem & Immunol, Ave Bandeirantes 3900, BR-14049900 Ribeirao Preto, SP - Brazil

^[2] Univ State Campinas, Inst Biol, Dept Anim Biol, Rua Monteiro Lobato 255, BR-13083862 Campinas, SP - Brazil

^[3] Univ Fed Ouro Preto, Inst Exact & Biol Sci, Campus Univ Morro Cruzeiro Bauxita, BR-35400000 Ouro Preto, MG - Brazil

^[4] Univ Franca Av Dr Armando Sales Oliveira, Res Grp Nat Prod, Ctr Res Sci & Technol, Av Dr Armando Sales Oliveira, 201 Parque Univ, BR-14404600 Franca, SP - Brazil

• Document type: Journal article
• Source: Acta Tropica; v. 217, MAY 2021.
• Web of Science Citations: 0

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-?) 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-? 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. (AU)

• FAPESP's process: 16/06769-2 - Molecular studies of deubiquitinating enzymes and its involvement in TGFb signaling pathway in the development of the reproductive system of Schistosoma mansoni
• Grantee: Vanderlei Rodrigues
• Support Opportunities: Regular Research Grants
• FAPESP's process: 17/07364-9 - Investigation of posttranslational histone modifications and co-regulators of expression in the Schistosoma mansoni stages
• Grantee: Fernanda Janku Cabral
• Support Opportunities: Regular Research Grants