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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

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

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Author(s):
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Carneiro, Vitor Coutinho [1, 2] ; de Abreu Silva, Isabel Caetano [1] ; Amaral, Murilo Sena [3] ; Pereira, Adriana S. A. [4, 3] ; Silveira, Gilbert Oliveira [4, 3] ; Pires, David da Silva [3] ; Verjovski-Almeida, Sergio [4, 3] ; Dekker, Frank J. [5] ; Rotili, Dante [6] ; Mai, Antonello [6] ; Lopes-Torres, Eduardo Jose [7] ; Robaa, Dina [8] ; Sippl, Wolfgang [8] ; Pierce, Raymond J. [9] ; Borrello, M. Teresa [10, 11] ; Ganesan, A. [12] ; Lancelot, Julien [9] ; Thiengo, Silvana [13] ; Fernandez, Monica Ammon [13] ; Revoredo Vicentino, Amanda Roberta [1] ; Mourao, Marina Moraes [14] ; Coelho, Fernanda Sales [14] ; Fantappie, Marcelo Rosado [1]
Total Authors: 23
Affiliation:
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[1] Univ Fed Rio de Janeiro, Ctr Ciencias Saude, Inst Bioquim Med Leopoldo de Meis, Programa Biol Mol & Biotecnol, Rio De Janeiro - Brazil
[2] German Canc Res Ctr, Div Epigenet, Heidelberg - Germany
[3] Inst Butantan, Lab Parasitol, Sao Paulo - Brazil
[4] Univ Sao Paulo, Inst Quim, Dept Bioquim, Sao Paulo - Brazil
[5] Univ Groningen, Dept Chem & Pharmaceut Biol, Groningen - Netherlands
[6] Sapienza Univ Rome, Dept Drug Chem & Technol, Rome - Italy
[7] Univ Estado Rio de Janeiro, Fac Ciencias Med, Lab Helmintol Romero Lascasas Porto, Rio De Janeiro - Brazil
[8] Martin Luther Univ Halle Wittenberg, Inst Pharm, Halle - Germany
[9] Univ Lille, CHU Lille, CNRS, INSERM, Inst Pasteur Lille, U1019, UMR 9017, CIIL, Lille - France
[10] Aix Marseille Univ, CNRS UMR 7258, INSERM U1068, Ctr Rech Cancerol Marseille CRCM, Parc Sci & Technol Luminy, Marseille - France
[11] Inst Paoli Calmettes, Parc Sci & Technol Luminy, Marseille - France
[12] Univ East Anglia, Sch Pharm, Norwich NR4 7TJ, Norfolk - England
[13] Fundacao Oswaldo Cruz, Lab Malacol, Inst Oswaldo Cruz, Rio De Janeiro - Brazil
[14] Fundacao Oswaldo Cruz, Inst Rene Rachou, Grp Helmintol & Malacol Med, Belo Horizonte, MG - Brazil
Total Affiliations: 14
Document type: Journal article
Source: PLoS Neglected Tropical Diseases; v. 14, n. 7 JUL 2020.
Web of Science Citations: 0
Abstract

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 againstSchistosoma mansoni. In the present study, we targeted theS.mansonilysine-specific demethylase 1 (SmLSD1), a transcriptional corepressor, using a novel and selective synthetic inhibitor, MC3935, which was used to treat schistosomula and adult wormsin 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 silicomolecular 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 andin vivotesting of selective schistosome LSD1 inhibitors. Author summary Schistosomiasis mansoni is a chronic and debilitating tropical disease caused by the helminthSchistosoma mansoni. The control and treatment of the disease rely almost exclusively on praziquantel (PZQ). Thus, there is an urgent need to search for promising protein targets to develop new drugs. Drugs that inhibit enzymes that modify the chromatin structure have been developed for a number of diseases. We and others have shown thatS.mansoniepigenetic enzymes are also potential therapeutic targets. Here we evaluated the potential of theS.mansonihistone demethylase LSD1 (SmLSD1) as a drug target. We reported the synthesis of a novel and potent LSD1 inhibitor, MC3935, and show that it selectively inhibited the enzymatic activity of SmLSD1. Treatment of juvenile or adult worms with MC3935 caused severe damage to the tegument of the parasites and compromised egg production. Importantly, MC3935 proved to be highly toxic toS.mansoni, culminating in the death of juvenile or adult worms within 96 h. Transcriptomic analysis of MC3935-treated parasites revealed changes in the gene expression of hundreds of genes involved in key biological processes. Importantly, SmLSD1 contains unique sequences within its polypeptide chain that could be explored to develop aS.mansoniselective drug. (AU)

FAPESP's process: 18/24015-0 - Functional characterization of long non-protein coding RNAs in Schistosoma mansoni
Grantee:Gilbert de Oliveira Silveira
Support type: Scholarships in Brazil - Doctorate