TY - JOUR
T1 - Pharmacological inhibition of lysine-specific demethylase 1 (LSD1) induces global transcriptional deregulation and ultrastructural alterations that impair viability in Schistosoma mansoni
AU - Coutinho Carneiro, Vitor
AU - de Abreu da Silva, Isabel Caetano
AU - Amaral, Murilo Sena
AU - Pereira, Adriana S.A.
AU - Silveira, Gilbert Oliveira
AU - Pires, David da Silva
AU - Verjovski-Almeida, Sergio
AU - Dekker, Frank J.
AU - Rotili, Dante
AU - Mai, Antonello
AU - Lopes-Torres, Eduardo José
AU - Robaa, Dina
AU - Sippl, Wolfgang
AU - Pierce, Raymond J.
AU - Borrello, M. Teresa
AU - Ganesan, A.
AU - Lancelot, Julien
AU - Thiengo, Silvana
AU - Fernandez, Monica Ammon
AU - Vicentino, Amanda Roberta Revoredo
AU - Mourão, Marina Moraes
AU - Coelho, Fernanda Sales
AU - Fantappié, Marcelo Rosado
PY - 2020/7/1
Y1 - 2020/7/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85087471659&partnerID=8YFLogxK
U2 - 10.1371/journal.pntd.0008332
DO - 10.1371/journal.pntd.0008332
M3 - Article
C2 - 32609727
AN - SCOPUS:85087471659
VL - 14
JO - PLoS Neglected Tropical Diseases
JF - PLoS Neglected Tropical Diseases
SN - 1935-2727
IS - 7
M1 - e0008332
ER -