Title :

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

Author(s) :

Coutinho Carneiro, Vitor [Auteur]
de Abreu da Silva, Isabel Caetano [Auteur]
Amaral, Murilo Sena [Auteur]
Instituto Butantan [São Paulo]
Pereira, Adriana [Auteur]
Universidade de São Paulo = University of São Paulo [USP]
Instituto Butantan [São Paulo]
Silveira, Gilbert Oliveira [Auteur]
Universidade de São Paulo = University of São Paulo [USP]
Instituto Butantan [São Paulo]
Pires, David da Silva [Auteur]
Instituto Butantan [São Paulo]
Verjovski-Almeida, Sergio [Auteur]
Universidade de São Paulo = University of São Paulo [USP]
Instituto Butantan [São Paulo]
Dekker, Frank [Auteur]
University of Groningen [Groningen]
Rotili, Dante [Auteur]
Università degli Studi di Roma "La Sapienza" = Sapienza University [Rome] [UNIROMA]
Mai, Antonello [Auteur]
Università degli Studi di Roma "La Sapienza" = Sapienza University [Rome] [UNIROMA]
Lopes-Torres, Eduardo José [Auteur]
Universidade do Estado do Rio de Janeiro [Rio de Janeiro] [UERJ]
Robaa, Dina [Auteur]
Martin-Luther-Universität Halle Wittenberg [MLU]
Sippl, Wolfgang [Auteur]
Martin-Luther-Universität Halle Wittenberg [MLU]
Pierce, Raymond [Auteur]
Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 [CIIL]
Borrello, M Teresa [Auteur]
Centre de Recherche en Cancérologie de Marseille [CRCM]
Ganesan, A [Auteur]
University of East Anglia [Norwich] [UEA]
Lancelot, Julien [Auteur]
Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 [CIIL]
Thiengo, Silvana [Auteur]
Fundação Oswaldo Cruz [FIOCRUZ]
Fernandez, Monica Ammon [Auteur]
Fundação Oswaldo Cruz [FIOCRUZ]
Vicentino, Amanda Roberta Revoredo [Auteur]
Mourão, Marina Moraes [Auteur]
Fundação Oswaldo Cruz [FIOCRUZ]
Coelho, Fernanda Sales [Auteur]
Fundação Oswaldo Cruz [FIOCRUZ]
Fantappié, Marcelo Rosado [Auteur correspondant]

Journal title :

PLoS Neglected Tropical Diseases

Pages :

e0008332

Publisher :

Public Library of Science

Publication date :

2020-07-01

ISSN :

1935-2727

HAL domain(s) :

Sciences du Vivant [q-bio]/Sciences pharmaceutiques/Pharmacologie
Sciences du Vivant [q-bio]/Microbiologie et Parasitologie/Parasitologie
Sciences du Vivant [q-bio]/Médecine humaine et pathologie/Maladies infectieuses

English abstract : [en]

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 ...
Show more >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.Show less >

Language :

Anglais

Peer reviewed article :

Oui

Audience :

Internationale

Popular science :

Non

Collections :

• Centre d'Infection et d'Immunité de Lille (CIIL) - U1019 - UMR 9017

Source :

Harvested from HAL