Pharmacological inhibition of lysine-specific demethylase 1 (LSD1) induces global transcriptional deregulation and ultrastructural alterations that impair viability in Schistosoma mansoni
Pharmacological inhibition of lysine-specific demethylase 1 (LSD1) induces global transcriptional deregulation and ultrastructural alterations that impair viability in Schistosoma mansoni
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 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. We synthesized a novel and potent LSD1 inhibitor, MC3935, which was used to treat schistosomula or 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. Author SummarySchistosomiasis mansoni is a chronic and debilitating tropical disease caused by the helminth Schistosoma 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 that S. mansoni epigenetic enzymes are also potential therapeutic targets. Here we evaluated the potential of the S. mansoni histone 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 to S. 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 a S. mansoni selective drug.
Pereira Adriana S.A.、Dekker Frank J.、Mai Antonello、Sippl Wolfgang、Thiengo Silvana、Vicentino Amanda Roberta Revoredo、Borrello M. Teresa、Fernandez Monica Ammon、Rotili Dante、Torres Eduardo Jos¨| Lopes、de Abreu da Silva Isabel Caetano、Silveira Gilbert O.、Mour?o Marina Moraes、Pierce Raymond J.、Verjovski-Almeida S¨|rgio、Robaa Dina、Ganesan A.、Carneiro Vitor Coutinho、Lancelot Julien、da Silva Pires David、Fantappi¨| Marcelo Rosado、Coelho Fernanda Sales、Amaral Murilo Sena
Laborat¨?rio de Parasitologia, Instituto Butantan||Departamento de Bioqu¨amica, Instituto de Qu¨amica, Universidade de S?o PauloDepartment of Chemical and Pharmaceutical Biology, University of GroningenDepartment of Drug Chemistry and Technologies, Sapienza University of RomeInstitute of Pharmacy, Martin Luther University of Halle-WittenbergLaborat¨?rio de Malacologia, Funda??o Oswaldo Cruz, Instituto Oswaldo CruzInstituto de Bioqu¨amica M¨|dica Leopoldo de Meis, Programa de Biologia Molecular e Biotecnologia, Centro de Ci¨oncias da Sa¨2de Universidade Federal do Rio de JaneiroCentre de Recherche en Canc¨|rologie de Marseille (CRCM) Aix-Marseille Universit¨| and Institut Paoli-Calmettes, Parc Scientifique et Technologique de LuminyLaborat¨?rio de Malacologia, Funda??o Oswaldo Cruz, Instituto Oswaldo CruzDepartment of Drug Chemistry and Technologies, Sapienza University of RomeLaborat¨?rio de Helmintologia Romero Lascasas Porto, Faculdade de Ci¨oncias M¨|dicas, Universidade do Estado do Rio de JaneiroInstituto de Bioqu¨amica M¨|dica Leopoldo de Meis, Programa de Biologia Molecular e Biotecnologia, Centro de Ci¨oncias da Sa¨2de Universidade Federal do Rio de JaneiroLaborat¨?rio de Parasitologia, Instituto Butantan||Departamento de Bioqu¨amica, Instituto de Qu¨amica, Universidade de S?o PauloGrupo de Helmintologia e Malacologia M¨|dica, Instituto Ren¨| Rachou, Funda??o Oswaldo CruzUniversit¨| de Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de LilleLaborat¨?rio de Parasitologia, Instituto Butantan||Departamento de Bioqu¨amica, Instituto de Qu¨amica, Universidade de S?o PauloInstitute of Pharmacy, Martin Luther University of Halle-WittenbergSchool of Pharmacy, University of East Anglia, Norwich Research ParkInstituto de Bioqu¨amica M¨|dica Leopoldo de Meis, Programa de Biologia Molecular e Biotecnologia, Centro de Ci¨oncias da Sa¨2de Universidade Federal do Rio de JaneiroUniversit¨| de Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de LilleLaborat¨?rio de Parasitologia, Instituto ButantanInstituto de Bioqu¨amica M¨|dica Leopoldo de Meis, Programa de Biologia Molecular e Biotecnologia, Centro de Ci¨oncias da Sa¨2de Universidade Federal do Rio de JaneiroGrupo de Helmintologia e Malacologia M¨|dica, Instituto Ren¨| Rachou, Funda??o Oswaldo CruzLaborat¨?rio de Parasitologia, Instituto Butantan
药学基础医学分子生物学
Pereira Adriana S.A.,Dekker Frank J.,Mai Antonello,Sippl Wolfgang,Thiengo Silvana,Vicentino Amanda Roberta Revoredo,Borrello M. Teresa,Fernandez Monica Ammon,Rotili Dante,Torres Eduardo Jos¨| Lopes,de Abreu da Silva Isabel Caetano,Silveira Gilbert O.,Mour?o Marina Moraes,Pierce Raymond J.,Verjovski-Almeida S¨|rgio,Robaa Dina,Ganesan A.,Carneiro Vitor Coutinho,Lancelot Julien,da Silva Pires David,Fantappi¨| Marcelo Rosado,Coelho Fernanda Sales,Amaral Murilo Sena.Pharmacological inhibition of lysine-specific demethylase 1 (LSD1) induces global transcriptional deregulation and ultrastructural alterations that impair viability in Schistosoma mansoni[EB/OL].(2025-03-28)[2025-08-02].https://www.biorxiv.org/content/10.1101/829549.点此复制
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