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

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Carneiro, Vitor Coutinho ; de Abreu Silva, Isabel Caetano ; Amaral, Murilo Sena ; Pereira, Adriana S. A. ; Silveira, Gilbert Oliveira ; Pires, David da Silva ; Verjovski-Almeida, Sergio ; Dekker, Frank J. ; Rotili, Dante ; Mai, Antonello ; Lopes-Torres, Eduardo Jose ; Robaa, Dina ; Sippl, Wolfgang ; Pierce, Raymond J. ; Borrello, M. Teresa ; Ganesan, A. ; Lancelot, Julien ; Thiengo, Silvana ; Fernandez, Monica Ammon ; Revoredo Vicentino, Amanda Roberta ; Mourao, Marina Moraes ; Coelho, Fernanda Sales ; Fantappie, Marcelo Rosado

• Document type: Journal article
• Source: PLoS Neglected Tropical Diseases; v. 14, n. 7, p. 29-pg., 2020-07-01.

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 Opportunities: Scholarships in Brazil - Doctorate