A5010022616- Parasites and Host Interactions
- Histone Deacetylase Inhibitors Research
- Biochemical and Molecular Research
- Enzyme function and inhibition
- Parasite Biology and Host Interactions
- Research on Leishmaniasis Studies
- Cholinesterase and Neurodegenerative Diseases
- Macrophage Migration Inhibitory Factor
- Epigenetics and DNA Methylation
- HIV/AIDS drug development and treatment
- Pharmacological Effects and Toxicity Studies
- Computational Drug Discovery Methods
- Malaria Research and Control
- Peptidase Inhibition and Analysis
- Signaling Pathways in Disease
- Trace Elements in Health
- Autophagy in Disease and Therapy
- Sirtuins and Resveratrol in Medicine
- Synthesis and Catalytic Reactions
- Parasitic infections in humans and animals
- Synthesis and biological activity
- Mitochondrial Function and Pathology
- Trypanosoma species research and implications
- Liver physiology and pathology
- Adenosine and Purinergic Signaling
Center for Infection and Immunity of Lille
2013-2021
Institut Pasteur de Lille
2011-2021
Centre National de la Recherche Scientifique
2011-2021
Université de Lille
2011-2021
Inserm
2011-2021
Centre Hospitalier Universitaire de Lille
2015-2021
Université Lille Nord de France
2011-2014
Institut Pasteur
2013-2014
The treatment of schistosomiasis, a disease caused by blood flukes parasites the Schistosoma genus, depends on intensive use single drug, praziquantel, which increases likelihood development drug-resistant parasite strains and renders search for new drugs strategic priority. Currently, inhibitors human epigenetic enzymes are actively investigated as novel anti-cancer have potential to be used anti-parasitic agents. Here, we report that mansoni histone deacetylase 8 (smHDAC8), most expressed...
Schistosomiasis is a major neglected parasitic disease that affects more than 265 million people worldwide and for which the control strategy consists of mass treatment with only available drug, praziquantel. In this study, series new benzohydroxamates were prepared as potent inhibitors Schistosoma mansoni histone deacetylase 8 (smHDAC8). Crystallographic analysis provided insights into inhibition mode smHDAC8 activity by these 3-amidobenzohydroxamates. The newly designed evaluated in...
Metal-dependent histone deacetylases (HDACs) are key epigenetic regulators that represent promising therapeutic targets for the treatment of numerous human diseases. Yet currently FDA-approved HDAC inhibitors nonspecifically target at least several 11 structurally similar but functionally different isozymes, which hampers their broad usage in clinical settings. Selective targeting single isozymes being developed, precise understanding molecular terms selectivity remains sparse. Here, we show...
Malaria, schistosomiasis and leishmaniases are among the most prevalent tropical parasitic diseases each requires new innovative treatments. Targeting essential parasite pathways, such as those that regulate gene expression cell cycle progression, is a key strategy for discovering drug leads. In this study, four clinically approved anti-cancer drugs (Vorinostat, Belinostat, Panobinostat Romidepsin) target histone/lysine deacetylase enzymes were examined in vitro activity against Plasmodium...
Background The chemotherapy of schistosomiasis currently depends on the use a single drug, praziquantel. In order to develop novel chemotherapeutic agents we are investigating enzymes involved in epigenetic modification chromatin. Sirtuins NAD+ dependent lysine deacetylases that wide variety cellular processes including histone deacetylation, and have been demonstrated be therapeutic targets various pathologies, cancer. Methodology, Principal Findings determine whether Schistosoma mansoni...
Schistosomiasis, caused by the parasitic flatworm Schistosoma mansoni and related species, is a tropical disease that affects over 200 million people worldwide. A new approach for targeting eukaryotic parasites to tackle their dynamic epigenetic machinery necessary extensive phenotypic changes during life cycle of parasite. Recently, we identified S. histone deacetylase 8 (smHDAC8) as potential target antiparasitic therapy. Here, present results on investigations focused set HDAC (histone...
Treatment and control of schistosomiasis relies on the only available drug, praziquantel, search for alternative chemotherapeutic agents is therefore urgent. Egg production required transmission immunopathology females S. mansoni lay 300 eggs daily. A large fraction total mRNA in mature female worm encodes one eggshell protein, Smp14. We report that nuclear receptors SmRXR1 SmNR1 regulate Smp14 transcription through recruitment two histone acetyltransferases (HATs), SmGCN5 SmCBP1. The...
Background Chemotherapy of schistosomiasis relies on a single drug, Praziquantel (PZQ) and mass-use this compound has led to emergence resistant strains Schistosoma mansoni, therefore pointing out the necessity find alternative drugs. Through their essential functions in development metabolism, receptor tyrosine kinases (RTK) could represent valuable drug targets for novel anti-schistosome chemotherapies. Taking advantage similarity between catalytic domains S. mansoni insulin receptors...
A promising means in the search of new small molecules for treatment schistosomiasis (amongst other parasitic ailments) is by targeting epigenome. In present study, a docking based virtual screening procedure using crystal structure histone deacetylase 8 from Schistosoma mansoni (smHDAC8) was designed. From developed protocol, we were able to identify eight novel N-(2,5-dioxopyrrolidin-3-yl)-n-alkylhydroxamate derivatives as smHDAC8 inhibitors with IC50 values ranging 4.4–20.3 µM against...
Protein kinases (PKs) are one of the largest protein families in most eukaryotic organisms. These enzymes involved control cell proliferation, differentiation and metabolism a large number anticancer drugs currently used directed against PKs. The structure function PKs well conserved throughout evolution. In schistosome parasites, were shown to be essential functions at every stage parasite life cycle, making these promising anti-parasite drug targets. this study, we tested panel commercial...
Only one drug is currently available for the treatment and control of schistosomiasis increasing risk selecting strains schistosome that are resistant to praziquantel means development new drugs urgent. With this objective we have chosen target enzymes modifying histones in particular histone acetyltransferases deacetylases (HDAC). Inhibitors HDACs (HDACi) under intense study as potential anti-cancer act via induction cell cycle arrest and/or apoptosis. Schistosomes like other parasites can...
Sirtuins are NAD(+)-dependent histone deacetylases (HDACs) that cleave off acetyl but also other acyl groups from the ϵ-amino group of lysines in histones and substrate proteins. Five sirtuin isoforms encoded genome parasitic pathogen Schistosoma mansoni. During its life cycle, S. mansoni undergoes drastic changes phenotype associated with epigenetic modifications. Previous work showed strong effects hSirt2 inhibitors on both worm span reproduction. Thus, we postulate smSirt2 as a new...
Abstract Schistosomiasis is a neglected parasitic disease that affects more than 265 million people worldwide and for which the control strategy relies on mass treatment with only one drug: praziquantel. Based 3‐chlorobenzothiophene‐2‐hydroxamic acid J1075 , series of hydroxamic acids different scaffolds were prepared as potential inhibitors Schistosoma mansoni histone deacetylase 8 ( Sm HDAC8). The crystal structures HDAC8 four provided insight into binding mode orientation molecules in...
The only drug currently available for treatment of the neglected disease Schistosomiasis is Praziquantel, and possible emergence resistance makes research on novel therapeutic agents necessary urgent. To this end, targeting Schistosoma mansoni epigenetic enzymes, which regulate parasitic life cycle, emerged as a promising approach. Due to strong effects human sirtuin inhibitors parasite survival reproduction, sirtuins were postulated potential targets. In vitro testing synthetic substrates...
Abstract Schistosomiasis is a neglected tropical disease caused by parasitic flatworms of the genus Schistosoma , which affects over 200 million people worldwide and leads to at least 300,000 deaths every year. In this study, initial screening revealed triazole‐based hydroxamate 2 b ( N ‐hydroxy‐1‐phenyl‐1 H ‐1,2,3‐triazole‐4‐carboxamide) exhibiting potent inhibitory activity toward novel antiparasitic target mansoni histone deacetylase 8 (smHDAC8) promising selectivity major human HDACs....
Treatment and control of schistosomiasis still rely on only one effective drug, praziquantel (PZQ) and, due to mass treatment, the increasing risk selecting for schistosome strains that are resistant PZQ has alerted investigators urgent need develop novel therapeutic strategies. The histone-modifying enzymes (HMEs) represent promising targets development epigenetic drugs against Schistosoma mansoni. In present study, we targeted S. mansoni lysine-specific demethylase 1 (SmLSD1), a...
Schistosoma mansoni histone deacetylase 8 ( Sm HDAC8) has been recently identified as a new potential target for the treatment of schistosomiasis. A series newly designed and synthesized alkoxyamide‐based hydrazide‐based HDAC inhibitors were tested inhibitory activity against HDAC8 human HDACs 1, 6, 8. The front runner compounds showed submicromolar modest preference over its orthologue hHDAC8. Docking studies provided insights into putative binding mode in allowed rationalization observed...
The trematode parasite, Schistosoma mansoni, has evolved to switch from oxidative phosphorylation glycolysis in the presence of glucose immediately after invading human host. This metabolic is dependent on extracellular concentration. Four transporters are encoded genome S. however, only two were shown facilitate diffusion. By modeling phase host infection, we showed that transporter transcript expression profiles recently transformed schistosomula have opposing responses increased...
Background Histone deacetylase 8 from Schistosoma mansoni (SmHDAC8) is essential to parasite growth and development within the mammalian host under investigation as a target for of selective inhibitors novel schistosomicidal drugs. Although some protein substrates partners human HDAC8 have been characterized, notably indicating role in function cohesin complex, nothing known biological SmHDAC8. Methodology/Principal findings We therefore employed two strategies characterize SmHDAC8...
The only drug for treatment of Schistosomiasis is Praziquantel, and the possible emergence resistance makes research on novel therapeutic agents necessary. Targeting Schistosoma mansoni epigenetic enzymes, which regulate parasitic life cycle, emerged as promising approach. Due to strong effects human Sirtuin inhibitors parasite survival reproduction, sirtuins were postulated targets. In vitro testing synthetic substrates S. 2 (SmSirt2) kinetic experiments a myristoylated peptide demonstrated...
Schistosoma mansoni histone deacetylase 8 (SmHDAC8) has elicited considerable interest as a target for drug discovery. Invalidation of its transcripts by RNAi leads to impaired survival the worms in infected mice and inhibition causes cell apoptosis death. To determine why it is promising therapeutic study currently unknown cellular signaling pathways involving this enzyme essential. Protein partners SmHDAC8 were previously identified yeast two-hybrid (Y2H) cDNA library screening mass...
The only drug for treatment of Schistosomiasis is Praziquantel, and the possible emergence resistance makes research on novel therapeutic agents necessary. Targeting Schistosoma mansoni epigenetic enzymes, which regulate parasitic life cycle, emerged as promising approach. Due to strong effects human Sirtuin inhibitors parasite survival reproduction, sirtuins were postulated targets. In vitro testing synthetic substrates S. 2 (SmSirt2) kinetic experiments a myristoylated peptide demonstrated...