Pharmacological inhibition of lysine-specific demethylase 1 (LSD1) induces global transcriptional deregulation and ultrastructural alterations that impair viability in Schistosoma mansoni.

Autor: Coutinho Carneiro V; Instituto de Bioquímica Médica Leopoldo de Meis, Programa de Biologia Molecular e Biotecnologia, Centro de Ciências da Saúde, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil., de Abreu da Silva IC; Instituto de Bioquímica Médica Leopoldo de Meis, Programa de Biologia Molecular e Biotecnologia, Centro de Ciências da Saúde, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil., Amaral MS; Laboratório de Parasitologia, Instituto Butantan, São Paulo, Brazil., Pereira ASA; Laboratório de Parasitologia, Instituto Butantan, São Paulo, Brazil.; Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, Brasil., Silveira GO; Laboratório de Parasitologia, Instituto Butantan, São Paulo, Brazil.; Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, Brasil., Pires DDS; Laboratório de Parasitologia, Instituto Butantan, São Paulo, Brazil., Verjovski-Almeida S; Laboratório de Parasitologia, Instituto Butantan, São Paulo, Brazil.; Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, Brasil., Dekker FJ; Department of Chemical and Pharmaceutical Biology, University of Groningen, Antonius Deusinglaan, AV Groningen, Netherlands., Rotili D; Department of Drug Chemistry and Technologies, Sapienza University of Rome, Rome, Italy., Mai A; Department of Drug Chemistry and Technologies, Sapienza University of Rome, Rome, Italy., Lopes-Torres EJ; Laboratório de Helmintologia Romero Lascasas Porto, Faculdade de Ciências Médicas, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, Brazil., Robaa D; Institute of Pharmacy, Martin Luther University of Halle-Wittenberg, Germany., Sippl W; Institute of Pharmacy, Martin Luther University of Halle-Wittenberg, Germany., Pierce RJ; Université de Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019-UMR 9017-CIIL-Centre d'Infection et d'Immunité de Lille, Lille, France., Borrello MT; Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Aix-Marseille Université and Institut Paoli-Calmettes, Parc Scientifique et Technologique de Luminy, Marseille, France., Ganesan A; School of Pharmacy, University of East Anglia, Norwich NR4 7TJ, United Kingdom., Lancelot J; Université de Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019-UMR 9017-CIIL-Centre d'Infection et d'Immunité de Lille, Lille, France., Thiengo S; Laboratório de Malacologia, Fundação Oswaldo Cruz, Instituto Oswaldo Cruz, Rio de Janeiro, Brazil., Fernandez MA; Laboratório de Malacologia, Fundação Oswaldo Cruz, Instituto Oswaldo Cruz, Rio de Janeiro, Brazil., Vicentino ARR; Instituto de Bioquímica Médica Leopoldo de Meis, Programa de Biologia Molecular e Biotecnologia, Centro de Ciências da Saúde, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil., Mourão MM; Grupo de Helmintologia e Malacologia Médica, Instituto René Rachou, Fundação Oswaldo Cruz, Belo Horizonte, Brazil., Coelho FS; Grupo de Helmintologia e Malacologia Médica, Instituto René Rachou, Fundação Oswaldo Cruz, Belo Horizonte, Brazil., Fantappié MR; Instituto de Bioquímica Médica Leopoldo de Meis, Programa de Biologia Molecular e Biotecnologia, Centro de Ciências da Saúde, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
Jazyk: angličtina
Zdroj: PLoS neglected tropical diseases [PLoS Negl Trop Dis] 2020 Jul 01; Vol. 14 (7), pp. e0008332. Date of Electronic Publication: 2020 Jul 01 (Print Publication: 2020).
DOI: 10.1371/journal.pntd.0008332
Abstrakt: Treatment and control of schistosomiasis still rely on only one effective drug, praziquantel (PZQ) and, due to mass treatment, the increasing risk of selecting for schistosome strains that are resistant to PZQ has alerted investigators to the urgent need to develop novel therapeutic strategies. The histone-modifying enzymes (HMEs) represent promising targets for the development of epigenetic drugs against Schistosoma mansoni. In the present study, we targeted the S. mansoni lysine-specific demethylase 1 (SmLSD1), a transcriptional corepressor, using a novel and selective synthetic inhibitor, MC3935, which was used to treat schistosomula and adult worms in vitro. By using cell viability assays and optical and electron microscopy, we showed that treatment with MC3935 affected parasite motility, egg-laying, tegument, and cellular organelle structures, culminating in the death of schistosomula and adult worms. In silico molecular modeling and docking analysis suggested that MC3935 binds to the catalytic pocket of SmLSD1. Western blot analysis revealed that MC3935 inhibited SmLSD1 demethylation activity of H3K4me1/2. Knockdown of SmLSD1 by RNAi recapitulated MC3935 phenotypes in adult worms. RNA-Seq analysis of MC3935-treated parasites revealed significant differences in gene expression related to critical biological processes. Collectively, our findings show that SmLSD1 is a promising drug target for the treatment of schistosomiasis and strongly support the further development and in vivo testing of selective schistosome LSD1 inhibitors.
Competing Interests: The authors have declared that no competing interests exist.
Databáze: MEDLINE
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