Author: "Paola B, Arimondo" - Searchworks@Jio Institute Digital Library Search Results

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1. Non-canonical functions of UHRF1 maintain DNA methylation homeostasis in cancer cells

Author: Kosuke Yamaguchi, Xiaoying Chen, Brianna Rodgers, Fumihito Miura, Pavel Bashtrykov, Frédéric Bonhomme, Catalina Salinas-Luypaert, Deis Haxholli, Nicole Gutekunst, Bihter Özdemir Aygenli, Laure Ferry, Olivier Kirsh, Marthe Laisné, Andrea Scelfo, Enes Ugur, Paola B. Arimondo, Heinrich Leonhardt, Masato T. Kanemaki, Till Bartke, Daniele Fachinetti, Albert Jeltsch, Takashi Ito, and Pierre-Antoine Defossez
Subjects: Science
Abstract: Abstract DNA methylation is an essential epigenetic chromatin modification, and its maintenance in mammals requires the protein UHRF1. It is yet unclear if UHRF1 functions solely by stimulating DNA methylation maintenance by DNMT1, or if it has important additional functions. Using degron alleles, we show that UHRF1 depletion causes a much greater loss of DNA methylation than DNMT1 depletion. This is not caused by passive demethylation as UHRF1-depleted cells proliferate more slowly than DNMT1-depleted cells. Instead, bioinformatics, proteomics and genetics experiments establish that UHRF1, besides activating DNMT1, interacts with DNMT3A and DNMT3B and promotes their activity. In addition, we show that UHRF1 antagonizes active DNA demethylation by TET2. Therefore, UHRF1 has non-canonical roles that contribute importantly to DNA methylation homeostasis; these findings have practical implications for epigenetics in health and disease.
Published: 2024
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2. Hemisynthetic alkaloids derived from trilobine are antimalarials with sustained activity in multidrug-resistant Plasmodium falciparum

Author: Flore Nardella, Irina Dobrescu, Haitham Hassan, Fabien Rodrigues, Sabine Thiberge, Liliana Mancio-Silva, Ambre Tafit, Corinne Jallet, Véronique Cadet-Daniel, Stéphane Goussin, Audrey Lorthiois, Yoann Menon, Nicolas Molinier, Dany Pechalrieu, Christophe Long, François Sautel, Mariette Matondo, Magalie Duchateau, Guillaume Médard, Benoit Witkowski, Artur Scherf, Ludovic Halby, and Paola B. Arimondo
Subjects: Multi-drug resistant organisms, Natural product chemistry, Applied microbiology, Microbiology parasite, Clinical microbiology, Science
Abstract: Summary: Malaria eradication requires the development of new drugs to combat drug-resistant parasites. We identified bisbenzylisoquinoline alkaloids isolated from Cocculus hirsutus that are active against Plasmodium falciparum blood stages. Synthesis of a library of 94 hemi-synthetic derivatives allowed to identify compound 84 that kills multi-drug resistant clinical isolates in the nanomolar range (median IC50 ranging from 35 to 88 nM). Chemical optimization led to compound 125 with significantly improved preclinical properties. 125 delays the onset of parasitemia in Plasmodium berghei infected mice and inhibits P. falciparum transmission stages in vitro (culture assays), and in vivo using membrane feeding assay in the Anopheles stephensi vector. Compound 125 also impairs P. falciparum development in sporozoite-infected hepatocytes, in the low micromolar range. Finally, by chemical pull-down strategy, we characterized the parasite interactome with trilobine derivatives, identifying protein partners belonging to metabolic pathways that are not targeted by the actual antimalarial drugs or implicated in drug-resistance mechanisms.
Published: 2023
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3. Epidrugs as Promising Tools to Eliminate Plasmodium falciparum Artemisinin-Resistant and Quiescent Parasites

Author: Thibaud Reyser, Lucie Paloque, Michel Nguyen, Jean-Michel Augereau, Matthew John Fuchter, Marie Lopez, Paola B. Arimondo, Storm Hassell-Hart, John Spencer, Luisa Di Stefano, and Françoise Benoit-Vical
Subjects: malaria, epigenetics, artemisinin resistance, quiescent parasites, epidrugs, Pharmacy and materia medica, RS1-441
Abstract: The use of artemisinin and its derivatives has helped reduce the burden of malaria caused by Plasmodium falciparum. However, artemisinin-resistant parasites are able, in the presence of artemisinins, to stop their cell cycles. This quiescent state can alter the activity of artemisinin partner drugs leading to a secondary drug resistance and thus threatens malaria eradication strategies. Drugs targeting epigenetic mechanisms (namely epidrugs) are emerging as potential antimalarial drugs. Here, we set out to evaluate a selection of various epidrugs for their activity against quiescent parasites, to explore the possibility of using these compounds to counter artemisinin resistance. The 32 chosen epidrugs were first screened for their antiplasmodial activity and selectivity. We then demonstrated, thanks to the specific Quiescent-stage Survival Assay, that four epidrugs targeting both histone methylation or deacetylation as well as DNA methylation decrease the ability of artemisinin-resistant parasites to recover after artemisinin exposure. In the quest for novel antiplasmodial drugs with new modes of action, these results reinforce the therapeutic potential of epidrugs as antiplasmodial drugs especially in the context of artemisinin resistance.
Published: 2023
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4. Direct Synthesis of Allyl Amines with 2‐Nitrosulfonamide Derivatives via the Tsuji‐Trost Reaction

Author: Corentin Bon, Dr. Paola B. Arimondo, and Dr. Ludovic Halby
Subjects: allylation reactions, conjugated allyl amines, nosyl groups, palladium, Tsuji-Trost reactions, Chemistry, QD1-999
Abstract: Abstract The Tsuji‐Trost Reaction is a palladium‐catalysed allylation of nucleophiles that consists in the reaction of a nitrogen, carbon or oxygen‐based nucleophiles with an allylic substrate bearing a leaving group. Here we present the use of 2‐nitrosulfonamide derivatives as nucleophile, which are reactive under mild conditions. 2‐nitrosulfonyl groups are well‐known dual protective activator groups easy to introduce in any type of amine substrates. The resulting 2‐nitrosulfonamide derivatives are ideal substrates for the Tsuji‐Trost reaction to afford a convenient and flexible access to primary and dissymmetric secondary allyl amines. The optimised procedure is flexible (for solvent, temperature, functional groups) and has been applied with good to excellent yield to access to a wide range of allyl amine derivatives.
Published: 2021
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5. The methylome of Biomphalaria glabrata and other mollusks: enduring modification of epigenetic landscape and phenotypic traits by a new DNA methylation inhibitor

Author: Nelia Luviano, Marie Lopez, Fleur Gawehns, Cristian Chaparro, Paola B. Arimondo, Slavica Ivanovic, Patrice David, Koen Verhoeven, Céline Cosseau, and Christoph Grunau
Subjects: DNMT inhibitors, 5-Methylcytosine, Mollusks, Invertebrates, Epigenetic inheritance, Epimutation, Genetics, QH426-470
Abstract: Abstract Background 5-Methylcytosine (5mC) is an important epigenetic mark in eukaryotes. Little information about its role exists for invertebrates. To investigate the contribution of 5mC to phenotypic variation in invertebrates, alteration of methylation patterns needs to be produced. Here, we apply new non-nucleoside DNA methyltransferase inhibitors (DNMTi) to introduce aleatory changes into the methylome of mollusk species. Results Flavanone inhibitor Flv1 was efficient in reducing 5mC in the freshwater snails Biomphalaria glabrata and Physa acuta, and to a lesser degree, probably due to lower stability in sea water, in the oyster Crassostrea gigas. Flv1 has no toxic effects and significantly decreased the 5mC level in the treated B. glabrata and in its offspring. Drug treatment triggers significant variation in the shell height in both generations. A reduced representation bisulfite-sequencing method called epiGBS corroborates hypomethylation effect of Flv1 in both B. glabrata generations and identifies seven Differential Methylated Regions (DMR) out of 32 found both in Flv1-exposed snails and its progeny, from which 5 were hypomethylated, demonstrating a multigenerational effect. By targeted bisulfite sequencing, we confirmed hypomethylation in a locus and show that it is associated with reduced gene expression. Conclusions Flv1 is a new and efficient DNMTi that can be used to induce transient and heritable modifications of the epigenetic landscape and phenotypic traits in mollusks, a phylum of the invertebrates in which epigenetics is understudied.
Published: 2021
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6. DNA methylome combined with chromosome cluster-oriented analysis provides an early signature for cutaneous melanoma aggressiveness

Author: Arnaud Carrier, Cécile Desjobert, Loic Ponger, Laurence Lamant, Matias Bustos, Jorge Torres-Ferreira, Rui Henrique, Carmen Jeronimo, Luisa Lanfrancone, Audrey Delmas, Gilles Favre, Antoine Daunay, Florence Busato, Dave SB Hoon, Jorg Tost, Chantal Etievant, Joëlle Riond, and Paola B Arimondo
Subjects: epigenomics, DNA methylation, chromosome clusters, patient outcome, oriented approach, melanoma, Medicine, Science, Biology (General), QH301-705.5
Abstract: Aberrant DNA methylation is a well-known feature of tumours and has been associated with metastatic melanoma. However, since melanoma cells are highly heterogeneous, it has been challenging to use affected genes to predict tumour aggressiveness, metastatic evolution, and patients’ outcomes. We hypothesized that common aggressive hypermethylation signatures should emerge early in tumorigenesis and should be shared in aggressive cells, independent of the physiological context under which this trait arises. We compared paired melanoma cell lines with the following properties: (i) each pair comprises one aggressive counterpart and its parental cell line and (ii) the aggressive cell lines were each obtained from different host and their environment (human, rat, and mouse), though starting from the same parent cell line. Next, we developed a multi-step genomic pipeline that combines the DNA methylome profile with a chromosome cluster-oriented analysis. A total of 229 differentially hypermethylated genes was commonly found in the aggressive cell lines. Genome localization analysis revealed hypermethylation peaks and clusters, identifying eight hypermethylated gene promoters for validation in tissues from melanoma patients. Five Cytosine-phosphate-Guanine (CpGs) identified in primary melanoma tissues were transformed into a DNA methylation score that can predict survival (log-rank test, p=0.0008). This strategy is potentially universally applicable to other diseases involving DNA methylation alterations.
Published: 2022
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7. DNA Methylation Bisubstrate Inhibitors Are Fast-Acting Drugs Active against Artemisinin-Resistant Plasmodium falciparum Parasites

Author: Flore Nardella, Ludovic Halby, Elie Hammam, Diane Erdmann, Véronique Cadet-Daniel, Roger Peronet, Didier Ménard, Benoit Witkowski, Salah Mecheri, Artur Scherf, and Paola B. Arimondo
Subjects: Chemistry, QD1-999
Published: 2019
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8. Malaria Parasite Stress Tolerance Is Regulated by DNMT2-Mediated tRNA Cytosine Methylation

Author: Elie Hammam, Ameya Sinha, Sebastian Baumgarten, Flore Nardella, Jiaqi Liang, Samia Miled, Frédéric Bonhomme, Diane Erdmann, Benoit Arcangioli, Paola B. Arimondo, Peter Dedon, Peter Preiser, and Artur Scherf
Subjects: malaria, tRNA, epitranscriptomic, RNA cytosine methylation, homeostasis, DNMT2, Microbiology, QR1-502
Abstract: ABSTRACT Malaria parasites need to cope with changing environmental conditions that require strong countermeasures to ensure pathogen survival in the human and mosquito hosts. The molecular mechanisms that protect Plasmodium falciparum homeostasis during the complex life cycle remain unknown. Here, we identify cytosine methylation of tRNAAsp (GTC) as being critical to maintain stable protein synthesis. Using conditional knockout (KO) of a member of the DNA methyltransferase family, called Pf-DNMT2, RNA bisulfite sequencing demonstrated the selective cytosine methylation of this enzyme of tRNAAsp (GTC) at position C38. Although no growth defect on parasite proliferation was observed, Pf-DNMT2KO parasites showed a selective downregulation of proteins with a GAC codon bias. This resulted in a significant shift in parasite metabolism, priming KO parasites for being more sensitive to various types of stress. Importantly, nutritional stress made tRNAAsp (GTC) sensitive to cleavage by an unknown nuclease and increased gametocyte production (>6-fold). Our study uncovers an epitranscriptomic mechanism that safeguards protein translation and homeostasis of sexual commitment in malaria parasites. IMPORTANCE P. falciparum is the most virulent malaria parasite species, accounting for the majority of the disease mortality and morbidity. Understanding how this pathogen is able to adapt to different cellular and environmental stressors during its complex life cycle is crucial in order to develop new strategies to tackle the disease. In this study, we identified the writer of a specific tRNA cytosine methylation site as a new layer of epitranscriptomic regulation in malaria parasites that regulates the translation of a subset of parasite proteins (>400) involved in different metabolic pathways. Our findings give insight into a novel molecular mechanism that regulates P. falciparum response to drug treatment and sexual commitment.
Published: 2021
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9. Anti-neoplastic and demethylating activity of a newly synthetized flavanone-derived compound in Renal Cell Carcinoma cell lines

Author: Ângela Marques-Magalhães, Inês Graça, Vera Miranda-Gonçalves, Rui Henrique, Marie Lopez, Paola B. Arimondo, and Carmen Jerónimo
Subjects: Renal Cell Carcinoma, DNA methylation, 3-nitroflavanones, DNMT inhibitors, Anticancer therapy, Therapeutics. Pharmacology, RM1-950
Abstract: Renal Cell Carcinoma (RCC) is on the top 10 of the most incident cancers worldwide, being a third of patients diagnosed with advanced disease, for which no curative therapies are currently available. Thus, new effective therapeutic strategies are urgently needed. Herein, we tested the antineoplastic effect of newly synthesized 3-nitroflavanones (MLo1302) on RCC cell lines. 786-O, Caki2, and ACHN cell lines were cultured and treated with newly synthesized 3-nitroflavanones. IC50 values were calculated based on the effect on cell viability assessed by MTT assay, after 72 h of exposure. MLo1302 displayed antineoplastic properties in RCC cell lines through marked reduction of cell viability, increased apoptosis and DNA damage, and morphometric alterations indicating a less aggressive phenotype. MLo1302 induced a significant reduction of global DNA methylation and DNMT mRNA levels, increasing global DNA hydroxymethylation and TET expression. Moreover, MLo1302 decreased DNMT3A activity in RCC cell lines, demethylated and re-expressed hypermethylated genes in CAM-generated tumors. A marked in vivo decrease in tumor growth and angiogenesis was also disclosed. MLo1302 disclosed antineoplastic and demethylating activity in RCC cell lines, constituting a potential therapeutic agent for RCC patients.
Published: 2021
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10. The Many Faces of EpigeneticsOxford, December 2017

Author: Paola B. Arimondo, Anouk Barberousse, and Gaëlle Pontarotti
Subjects: epigenetics, definition, explanatory tools, molecular tools, society, environment, Genetics, QH426-470
Abstract: The conference ‘The Many Faces of Epigenetics: Multidisciplinary Perspectives “over” Genetics’ was held in Oxford (6–8 December 2017) and offered a valuable window into the domain of Epigenetics and its promises. The workshop revealed that, among a wealth of discourses about Epigenetics, it is not so easy to decipher which discourses are to be trusted. Because Epigenetics is a rather old notion that has generated many debates and promises, defining precisely what has changed and where we are currently is a challenge in itself. Interestingly, the conference allowed debates beyond statements such as ‘If you don’t know the cause, you say it’s epigenetic’ (Deichmann 2016), pointing out that the lack of a precise definition of Epigenetics was no hindrance to the discussions. Finally, it highlighted the grounds of (dis)agreement among communities of natural and social scientists; but eventually the discussions showed that epigenetic tools open the path to new topics and challenges that are awaiting us.
Published: 2019
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11. Demethylation by low-dose 5-aza-2′-deoxycytidine impairs 3D melanoma invasion partially through miR-199a-3p expression revealing the role of this miR in melanoma

Author: Cécile Desjobert, Arnaud Carrier, Audrey Delmas, Diego M. Marzese, Antoine Daunay, Florence Busato, Arnaud Pillon, Jörg Tost, Joëlle Riond, Gilles Favre, Chantal Etievant, and Paola B. Arimondo
Subjects: DNA methylation, microRNA, Melanoma aggressiveness, Epigenetics, Medicine, Genetics, QH426-470
Abstract: Abstract Background Efficient treatments against metastatic melanoma dissemination are still lacking. Here, we report that low-cytotoxic concentrations of 5-aza-2′-deoxycytidine, a DNA demethylating agent, prevent in vitro 3D invasiveness of metastatic melanoma cells and reduce lung metastasis formation in vivo. Results We unravelled that this beneficial effect is in part due to MIR-199A2 re-expression by promoter demethylation. Alone, this miR showed an anti-invasive and anti-metastatic effect. Throughout integration of micro-RNA target prediction databases with transcriptomic analysis after 5-aza-2′-deoxycytidine treatments, we found that miR-199a-3p downregulates set of genes significantly involved in invasion/migration processes. In addition, analysis of data from melanoma patients showed a stage- and tissue type-dependent modulation of MIR-199A2 expression by DNA methylation. Conclusions Thus, our data suggest that epigenetic- and/or miR-based therapeutic strategies can be relevant to limit metastatic dissemination of melanoma.
Published: 2019
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12. Disruptor of telomeric silencing 1-like (DOT1L): disclosing a new class of non-nucleoside inhibitors by means of ligand-based and structure-based approaches.

Author: Manuela Sabatino, Dante Rotili, Alexandros Patsilinakos, Mariantonietta Forgione, Daniela Tomaselli, Fréderic Alby, Paola B. Arimondo, Antonello Mai, and Rino Ragno
Published: 2018
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13. Design and synthesis of naturally-inspired SARS-CoV-2 inhibitors

Author: Haitham Hassan, Jeanne Chiavaralli, Afnan Hassan, Loay Bedda, Tim Krischuns, Kuang-Yu Chen, Alice Shi Ming Li, Adrien Delpal, Etienne Decroly, Masoud Vedadi, Nadia Naffakh, Fabrice Agou, Sergio Mallart, Reem K. Arafa, Paola B. Arimondo, Chimie biologique épigénétique - Epigenetic Chemical Biology (EpiCBio), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Criblage chémogénomique et biologique (Plateforme) - Chemogenomic and Biological Screening Platform (PF-CCB), Zewail City of Science and Technology, Biologie des ARN et virus influenza - RNA Biology of Influenza Virus (CNRS-UMR3569), University of Toronto, Aix Marseille Université (AMU), Architecture et fonction des macromolécules biologiques (AFMB), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Fondation de France grant Programme Féderateur de Recherche sur SARS-CoV2 & COVID-19 PRF7 SARS-CoV2 drugpipeline project (to PBA). Vedadi's lab is funded by the US NIH 1U19AI171110-01.The 'URGENCE COVID-19' fundraising campaign of Institut Pasteur and by the Agence Nationale de la Recherche (grants ANR-18-CE18-0026, ANR-18-CE18-0028 and ANR-10-LABX-62-IBEID), The authors thank Dr Benjamin BARDIAUX, Structural Bioinformatics Laboratory, Institute Pasteur, for constructive proofreading of the in silico studies part. The authors thank the Institut Pasteur and Fondation de France grants for the installation and the Drug pipeline against SARS-CoV-2 project. Sylvain Paisant and Marine Ghazarian are acknowledged for providing technical help for the Mpro cell-based assay., ANR-18-CE18-0026,microFLU-REASSORT,Analyse à haut-débit du réassortiment entre virus influenza A par microfluidique et séquençage du génome ARN de virus uniques - application à l'analyse du risque pandémique et à l'optimisation des virus candidats vaccins(2018), and ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010)
Subjects: Pharmacology, [SDV]Life Sciences [q-bio], Organic Chemistry, Drug Discovery, Pharmaceutical Science, Molecular Medicine, Biochemistry
Abstract: International audience; A naturally inspired chemical library of 25 molecules was synthesised guided by 3-D dimensionality and natural product likeness proved to have antiviral activity against SARS-CoV-2.
Published: 2023

14. Synthesis and Biological Activity of a Cytostatic Inhibitor of MLLr Leukemia Targeting the DOT1L Protein

Author: Corentin Bon, Yang Si, Melanie Pernak, Magdalena Barbachowska, Eva Levi-Acobas, Veronique Cadet Daniel, Corinne Jallet, Dusan Ruzic, Nemanja Djokovic, Teodora Djikić, Katarina Nikolic, Ludovic Halby, and Paola B. Arimondo
Subjects: MLL rearranged leukemia, DOT1L, histone methylation, rational drug design, HMT inhibitors, bisubstrates, Organic chemistry, QD241-441
Abstract: Histone methyltransferase DOT1L catalyzes mono-, di- and trimethylation of histone 3 at lysine residue 79 (H3K79) and hypermethylation of H3K79 has been linked to the development of acute leukemias characterized by the MLL (mixed-lineage leukemia) rearrangements (MLLr cells). The inhibition of H3K79 methylation inhibits MLLr cells proliferation, and an inhibitor specific for DOT1L, pinometostat, was in clinical trials (Phase Ib/II). However, the compound showed poor pharmacological properties. Thus, there is a need to find new potent inhibitors of DOT1L for the treatment of rearranged leukemias. Here we present the design, synthesis, and biological evaluation of a small molecule that inhibits in the nM level the enzymatic activity of hDOT1L, H3K79 methylation in MLLr cells with comparable potency to pinometostat, associated with improved metabolic stability and a characteristic cytostatic effect.
Published: 2021
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15. An epigenetic molluscicide

Author: Nelia Luviano, Ludovic Halby, Corinne Jallet, Paola B. Arimondo, Celine Cosseau, Christoph Grunau, Interactions Hôtes-Pathogènes-Environnements (IHPE), Université de Perpignan Via Domitia (UPVD)-Institut Français de Recherche pour l'Exploitation de la Mer (IFREMER)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Chimie biologique épigénétique - Epigenetic Chemical Biology (EpiCBio), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), This study is set within the framework of the « Laboratoire d’Excellence (LabEx) » TULIP (ANR-10-LABX-41) and CeMEB (ANR- 10-LABX-04-01). N.L. was supported by a PhD grant of the Region Occitanie, France and the UPVD, ANR-10-LABX-0041,TULIP,Towards a Unified theory of biotic Interactions: the roLe of environmental(2010), and ANR-10-LABX-0004,CeMEB,Mediterranean Center for Environment and Biodiversity(2010)
Subjects: molluscicide, [SDV.BA.ZI]Life Sciences [q-bio]/Animal biology/Invertebrate Zoology, schistosomiases, epigenetics, DNA methylation inhibitor, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, Biomphalaria glabrata
Abstract: Biomphalaria glabratais a fresh-water mollusk that serves as obligatory intermediate host toSchistosoma mansoni, agent of the neglected tropical disease schistosomiasis that affects roughly 250 Mio people. One of the ways to control the pathogenic agent is to interrupt the life cycle by eliminating the intermediate snail host though foal treatment of water bodies with molluscicides. Currently recommended molluscicides were developed in the 1950ths and lack sufficient specificity, e.g., they are toxic to fish. To provide new lead compounds for the development of a new type of molluscicides we used a rational approach based on the hypotheses that interfering with an important epigenetic mark, DNA methylation, would impede development of the snail host. We present here the compound 29, analogues-based compound that mimic substrates of DNA methyltransferases. We show that compound 29 has (i) low cytotoxicity for human cells, (ii) it inhibits DNA methylation, and (iii) it decreases fecundity inB.glabrata. It is therefore conceivable to produce compounds that act as specific epigenetic molluscicides.
Published: 2023

16. Plasmodium falciparum Eukaryotic Translation Initiation Factor 3 is Stabilized by Quinazoline-Quinoline Bisubstrate Inhibitors

Author: Irina Dobrescu, Elie Hammam, Jerzy M. Dziekan, Aurélie Claës, Ludovic Halby, Peter Preiser, Zbynek Bozdech, Paola B. Arimondo, Artur Scherf, and Flore Nardella
Subjects: Infectious Diseases
Published: 2023

17. Supplementary Materials and Methods from A Quinoline-Based DNA Methyltransferase Inhibitor as a Possible Adjuvant in Osteosarcoma Therapy

Author: Katia Scotlandi, Antonello Mai, Pier-Luigi Lollini, Patrizia Nanni, Piero Picci, Clara Guerzoni, Michela Pasello, Paola B. Arimondo, Giulia Stazi, Roberta Mazzone, Clemens Zwergel, Lorena Landuzzi, Giordano Nicoletti, Camilla Cristalli, Sergio Valente, and Maria Cristina Manara
Abstract: Additional materials and methods
Published: 2023

18. Figure S1 from A Quinoline-Based DNA Methyltransferase Inhibitor as a Possible Adjuvant in Osteosarcoma Therapy

Author: Katia Scotlandi, Antonello Mai, Pier-Luigi Lollini, Patrizia Nanni, Piero Picci, Clara Guerzoni, Michela Pasello, Paola B. Arimondo, Giulia Stazi, Roberta Mazzone, Clemens Zwergel, Lorena Landuzzi, Giordano Nicoletti, Camilla Cristalli, Sergio Valente, and Maria Cristina Manara
Abstract: Silencing of DNMTs inhibits cell proliferation, induces osteoblastic differentiation and enhances DXR sensitivity
Published: 2023

19. Table S1 from A Quinoline-Based DNA Methyltransferase Inhibitor as a Possible Adjuvant in Osteosarcoma Therapy

Author: Katia Scotlandi, Antonello Mai, Pier-Luigi Lollini, Patrizia Nanni, Piero Picci, Clara Guerzoni, Michela Pasello, Paola B. Arimondo, Giulia Stazi, Roberta Mazzone, Clemens Zwergel, Lorena Landuzzi, Giordano Nicoletti, Camilla Cristalli, Sergio Valente, and Maria Cristina Manara
Abstract: Inhibitory activity of MC3343 against human DNMT1 and human DNMT3a
Published: 2023

20. Data from A Quinoline-Based DNA Methyltransferase Inhibitor as a Possible Adjuvant in Osteosarcoma Therapy

Author: Katia Scotlandi, Antonello Mai, Pier-Luigi Lollini, Patrizia Nanni, Piero Picci, Clara Guerzoni, Michela Pasello, Paola B. Arimondo, Giulia Stazi, Roberta Mazzone, Clemens Zwergel, Lorena Landuzzi, Giordano Nicoletti, Camilla Cristalli, Sergio Valente, and Maria Cristina Manara
Abstract: The identification of new therapeutic strategies against osteosarcoma, the most common primary bone tumor, continues to be a primary goal to improve the outcomes of patients refractory to conventional chemotherapy. Osteosarcoma originates from the transformation of mesenchymal stem cells (MSC) and/or osteoblast progenitors, and the loss of differentiation is a common biological osteosarcoma feature, which has strong significance in predicting tumor aggressiveness. Thus, restoring differentiation through epigenetic reprogramming is potentially exploitable for therapeutic benefits. Here, we demonstrated that the novel nonnucleoside DNMT inhibitor (DNMTi) MC3343 affected tumor proliferation by blocking osteosarcoma cells in G1 or G2–M phases and induced osteoblastic differentiation through the specific reexpression of genes regulating this physiologic process. Although MC3343 has a similar antiproliferative effect as 5azadC, the conventional FDA-approved nucleoside inhibitor of DNA methylation, its effects on cell differentiation are distinct. Induction of the mature osteoblast phenotype coupled with a sustained cytostatic response was also confirmed in vivo when MC3343 was used against a patient-derived xenograft (PDX). In addition, MC3343 displayed synergistic effects with doxorubicin and cisplatin (CDDP), two major chemotherapeutic agents used to treat osteosarcoma. Specifically, MC3343 increased stable doxorubicin bonds to DNA, and combined treatment resulted in sustained DNA damage and increased cell death. Overall, this nonnucleoside DNMTi is an effective novel agent and is thus a potential therapeutic option for patients with osteosarcoma who respond poorly to preadjuvant chemotherapy. Mol Cancer Ther; 17(9); 1881–92. ©2018 AACR.
Published: 2023

21. EFMC: Trends in Medicinal Chemistry and Chemical Biology

Author: Yves P. Auberson, Paola B. Arimondo, Maria Duca, Sebastian Essig, Uwe Grether, Arne C. Rufer, Gianluca Sbardella, Ulrich Schopfer, Antoni Torrens, Mario van der Stelt, Boris Vauzeilles, Olalla Vázquez, and Andrew X. Zhang
Subjects: Organic Chemistry, Molecular Medicine, Molecular Biology, Biochemistry
Published: 2023

22. Targeting Germ Cell Tumors with the Newly Synthesized Flavanone-Derived Compound MLo1302 Efficiently Reduces Tumor Cell Viability and Induces Apoptosis and Cell Cycle Arrest

Author: João Lobo, Ana Rita Cardoso, Vera Miranda-Gonçalves, Leendert H. J. Looijenga, Marie Lopez, Paola B. Arimondo, Rui Henrique, and Carmen Jerónimo
Subjects: epidrugs, testicular germ cell tumors, DNA methylation, cell differentiation, drug design, Pharmacy and materia medica, RS1-441
Abstract: Less toxic treatment strategies for testicular germ cell tumor (TGCT) patients are needed, as overtreatment is a concern due to the long-term side effects of platin-based chemotherapy. Although clinical benefit from classical hypomethylating agents has to date been limited, TGCTs show an abnormal DNA methylome indicating the potential of treating TGCTs with hypomethylating drugs. We tested, for the first time in TGCT cell lines, a new synthetic flavonoid compound (MLo1302) from the 3-nitroflavanone family of DNA methyltransferase (DNMT) inhibitors. We show that MLo1302 reduces cell viability (including of cisplatin resistant cell line NCCIT-R), with IC50s (inhibitory concentration 50) within the nanomolar range for NCCIT and NTERA-2 cells, and proved its cytotoxic effect. Exposure to MLo1302 reduced DNMT protein expression, similar to decitabine, and showed a partial effect in cell differentiation, reducing protein expression of pluripotency markers. RT2 profiler expression array indicated several dysregulated targets, related to activation of apoptosis, differentiation, and cell cycle arrest. We validated these data by showing increased apoptosis, increased protein expression of cleaved caspase 8 and activated caspase 2, and reduced proliferation (BrdU assay), with increase in CDKN1A and decrease in MIB-1 expression. Therefore, synthetic drugs designed to target DNA methylation in cells may uncover effective treatments for TGCT patients.
Published: 2021
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23. Quinazoline-quinoline bisubstrate inhibitors target eukaryotic translation initiation factor 3 inPlasmodium falciparum

Author: Irina Dobrescu, Elie Hammam, Jerzy M. Dziekan, Aurélie Claës, Ludovic Halby, Peter Preiser, Zbynek Bozdech, Paola B. Arimondo, Artur Scherf, and Flore Nardella
Abstract: Malaria drug resistance is hampering the fight against the deadliest parasitic disease affecting over 200 million people worldwide. We recently developed quinoline-quinazoline-based inhibitors (as compound70) as promising new antimalarials. Here we aimed to investigate their mechanism of action by using Thermal Proteome Profiling (TPP). The eukaryotic translation initiation factor 3 (EIF3i) subunit I was identified as the main target of the inhibitor inP. falciparum. This protein is not a known drug target in malaria parasites.P. falciparumparasite lines were generated expressing either a HA tag or an inducible knockdown of the PfEIF3i gene to further characterize the target protein. PfEIF3i was stabilized in presence of the compound70in a cellular thermal shift-western blot assay, confirming that PfEIF3i is a target of quinoline-quinazoline-based inhibitors. In addition, PfEIF3i-inducible knock-down blocks intra-erythrocytic development in the trophozoite stage indicating that it has a vital function. We show that PfEIF3i is mostly expressed in late intraerythrocytic stages and localizes in the cytoplasm. Previous mass spectrometry reports show that EIF3i is expressed in all parasite life cycle stages. Hence, quinoline-quinazoline-based inhibitors allowed to identify PfEIF3i as a valuable target for the design of new antimalarial drugs active all along the life cycle of the parasite.
Published: 2022

24. Inhibitors of DNA Methylation

Author: Marie, Lopez, Julie, Gilbert, Jean, Contreras, Ludovic, Halby, and Paola B, Arimondo
Subjects: Histone Deacetylase Inhibitors, Neoplasms, Humans, DNA (Cytosine-5-)-Methyltransferases, DNA Methylation, Enzyme Inhibitors, DNA Modification Methylases
Abstract: DNA methylation is involved in numerous biological processes and is deregulated in human diseases. The modulation of the activity of the enzymes and proteins in charge of DNA methylation, for example, DNA methyltransferases (DNMTs), can represent a powerful strategy to alter DNA methylation patterns and restore biological processes that are aberrant in diseases. In this chapter, we present examples of inhibitors of DNMTs (DNMTi). We review their fields of application either as therapeutic molecules, for example, in cancers, cardiovascular, neurological, and infectious diseases or as bioengineering tools. Finally, novel strategies to target DNA methylation and overcome the limits of single DNMT inhibitors will be described. These strategies consist in either targeting the methyl group reader proteins rather than targeting directly DNMTs or to combine within the same molecule a DNMT inhibitor with an additional active moiety, e.g., HDAC inhibitor, to improve efficacy and lower secondary effect of such drug.
Published: 2022

25. Correction: Identification of a novel quinoline-based DNA demethylating compound highly potent in cancer cells

Author: Clemens Zwergel, Michael Schnekenburger, Federica Sarno, Cecilia Battistelli, Maria Cristina Manara, Giulia Stazi, Roberta Mazzone, Rossella Fioravanti, Christina Gros, Frédéric Ausseil, Cristina Florean, Angela Nebbioso, Raffaele Strippoli, Toshikazu Ushijima, Katia Scotlandi, Marco Tripodi, Paola B. Arimondo, Lucia Altucci, Marc Diederich, Antonello Mai, and Sergio Valente
Subjects: Genetics, Molecular Biology, Genetics (clinical), Developmental Biology
Published: 2022

26. Hemisynthetic derivatives of the natural alkaloid trilobine are fast-acting antimalarial compounds with sustained activity in multi-drug resistant P. falciparum isolates

Author: Flore Nardella, Irina Dobrescu, Haitham Hassan, Fabien Rodrigues, Sabine Thiberge, Liliana Mancio Silva, Ambre Tafit, Corinne Jallet, Véronique Cadet-Daniel, Stéphane Goussin, Audrey Lorthiois, Yoann Menon, Nicolas Molinier, Dany Pechalrieu, Christophe Long, François Sautel, Mariette Matondo, Magalie Duchateau, Guillaume Medard, Benoit Witkowski, Artur Scherf, Ludovic Halby, and Paola B. Arimondo
Abstract: Malaria eradication requires the development of new drugs to combat drug-resistant parasites. The search for new chemical scaffolds that target novel pathways of the human malaria parasite Plasmodium falciparum is of highest priority. We identified bisbenzylisoquinoline alkaloids isolated from Cocculus hirsutus. (trilobine derivatives) as active in the nanomolar range against P. falciparum blood stages. Synthesis of a library of 94 hemi-synthetic derivatives allowed us to identify compound 84 that kills multi-drug resistant clinical isolates in the nanomolar range (median IC50 ranging from 35-88nM). Efforts were made to obtain compounds with significantly improved preclinical properties. Out of those, compound 125 delays the onset of parasitemia in P. berghei infected mice and inhibits P. falciparum transmission stages in vitro (culture assays) and in vivo using membrane feeding assay in the Anopheles stephensi vector. Compound 125 also impairs P. falciparum development in sporozoite-infected hepatocytes, in the low micromolar range. Finally, we used a chemical pull-down strategy to identify potential protein targets of this chemical family. Mass spectrometry analysis identified the parasite interactome with trilobine derivatives, identifying protein partners belonging to metabolic pathways that have not been previously targeted by antimalarial drugs or implicated in drug-resistance mechanisms.
Published: 2022

27. Author response: DNA methylome combined with chromosome cluster-oriented analysis provides an early signature for cutaneous melanoma aggressiveness

Author: Arnaud Carrier, Cécile Desjobert, Loic Ponger, Laurence Lamant, Matias Bustos, Jorge Torres-Ferreira, Rui Henrique, Carmen Jeronimo, Luisa Lanfrancone, Audrey Delmas, Gilles Favre, Antoine Daunay, Florence Busato, Dave SB Hoon, Jorg Tost, Chantal Etievant, Joëlle Riond, and Paola B Arimondo
Published: 2022

28. Epigenetically regulated PCDHB15 impairs aggressiveness of metastatic melanoma cells

Author: Arnaud Carrier, Cécile Desjobert, Valérie Lobjois, Lise Rigal, Florence Busato, Jörg Tost, Miquel Ensenyat-Mendez, Diego M. Marzese, Anne Pradines, Gilles Favre, Laurence Lamant, Luisa Lanfrancone, Chantal Etievant, Paola B. Arimondo, Joëlle Riond, Pharmacochimie de la Régulation Epigénétique du Cancer (ETaC), PIERRE FABRE-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Josep Carreras Leukaemia Research Institute (IJC), Institut des Technologies Avancées en sciences du Vivant (ITAV), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Biologie Cellulaire et Moléculaire du Contrôle de la Prolifération (LBCMCP), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre de Biologie Intégrative (CBI), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Centre National de Recherche en Génomique Humaine (CNRGH), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Université Paris-Saclay, Fundació Institut d'Investigació Sanitària Illes Balears (IdISBa), Centre de Recherches en Cancérologie de Toulouse (CRCT), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Claudius Regaud, Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Istituto Europeo di Oncologia [Milano] (IEO), Chimie biologique épigénétique - Epigenetic Chemical Biology (EpiCBio), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), This work was supported to P.B.A. by Centre National de la Recherche Scientifique (CNRS) [ATIP], Région Midi Pyrenées [Equipe d’Excellence and FEDER CNRS/Région Midi Pyrenées], Fondation InNaBioSanté and by the National Research Agency (ANR: Agence Nationale de la Recherche) 'Investissement d’avenir' [ANR-11-PHUC-001, CAPTOR research program], Comité de Paris de la Ligue contre la Cancer (project Epi-Med 2020-2021, RS20/75-82 and RS21/75-31 and the Pasteur Institute of Paris., and ANR-11-PHUC-0001,CAPTOR,Cancer et Pharmacologie : Projet de Toulouse-Oncopole et de sa Région(2011)
Subjects: Lung Neoplasms, tumor suppressor, [SDV]Life Sciences [q-bio], Exons, aggressiveness, DNA Methylation, Genetics, [CHIM]Chemical Sciences, Humans, protocadherin, Molecular Biology, Melanoma, Genetics (clinical), Developmental Biology, Signal Transduction
Abstract: The protocadherin proteins are cell adhesion molecules at the crossroad of signaling pathways playing a major role in neuronal development. It is now understood that their role as signaling hubs is not only important for the normal physiology of cells but also for the regulation of hallmarks of cancerogenesis. Importantly, protocadherins form a cluster of genes that are regulated by DNA methylation. We have identified for the first time that PCDHB15 gene is DNA-hypermethylated on its unique exon in the metastatic melanoma-derived cell lines and patients’ metastases compared to primary tumors. This DNA hypermethylation silences the gene, and treatment with the DNA demethylating agent 5-aza-2′-deoxycytidine reinduces its expression. We explored the role of PCDHB15 in melanoma aggressiveness and showed that overexpression impairs invasiveness and aggregation of metastatic melanoma cells in vitro and formation of lung metastasis in vivo. These findings highlight important modifications of the methylation of the PCDHβ genes in melanoma and support a functional role of PCDHB15 silencing in melanoma aggressiveness.
Published: 2022

29. Quinazoline-based analog of adenine as an antidote against MLL-rearranged leukemia cells: synthesis, inhibition assays and docking studies

Author: Corentin Bon, Magdalena Barbachowska, Nemanja Djokovic, Dusan Ruzic, Yang Si, Laura Soresinetti, Corinne Jallet, Ambre Tafit, Ludovic Halby, Katarina Nikolic, Paola B Arimondo, Chimie biologique épigénétique - Epigenetic Chemical Biology (EpiCBio), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Ecole doctorale Médicament -Toxicologie - Chimie - Imageries [Université de Paris] (ED 563), Université Paris Cité (UPCité), University of Belgrade [Belgrade], and Région Ile de France supported the research with a Ph.D. fellowship to CB (ARDoC) and DIM OneHealth Investissements to PBA. Le Comité de Paris de la Ligue contre la Cancer (project Epi-Med 2020-2021) to PBA. Hubert Curien Partnership Project for collaboration France-Serbia 2020-2022 (Program Pavle Savic 2020) to PBA and KN.The authors collaborated in the frame of the EU COST CM1406 Epigenetic Chemical Biology program.DR, NDj and KN acknowledge project of Ministry of Science and Technological Development of the Republic of Serbia, Faculty of Pharmacy, Contract No. 451-03-9/2021-14/200161.
Subjects: Pharmacology, Leukemia, epigenetics, Adenine, Antidotes, DOT1L, Histone-Lysine N-Methyltransferase, bisubstrate inhibitors, Molecular Docking Simulation, chemical probes, Drug Discovery, adenine analogs, Quinazolines, [CHIM]Chemical Sciences, Molecular Medicine, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, adenine analogues, MLLr leukemia, MLLr leukaemia
Abstract: International audience; Background: Post-translational modifications of histones constitute a dynamic process impacting gene expression. A well-studied modification is lysine methylation. Among the lysine histone methyltransferases, DOT1L is implicated in various diseases, making it a very interesting target for drug discovery. DOT1L has two substrates, the SAM cofactor that gives the methyl group and the lysine H3K79 substrate. Results: Using molecular docking, the authors explored new bisubstrate analogs to enlarge the chemical landscape of DOT1L inhibitors. The authors showed that quinazoline can successfully replace the adenine in the design of bisubstrate inhibitors of DOT1L, showing similar activity compared with the adenine derivative but with diminished cytotoxicity. Conclusion: The docking model is validated together with the use of quinazoline in the design of bisubstrate inhibitors.
Published: 2022

30. Inhibitors of DNA Methylation

Author: Marie Lopez, Julie Gilbert, Jean Contreras, Ludovic Halby, and Paola B. Arimondo
Published: 2022

31. Identification of Chemical Probes Targeting MBD2

Author: Diane Erdmann, Jean Contreras, Rémy A. Le Meur, Bruno Vitorge, Vincent Saverat, Ambre Tafit, Corinne Jallet, Véronique Cadet-Daniel, Corentin Bon, Phannarath Phansavath, Virginie Ratovelomanana-Vidal, Albert Jeltsch, Sophie Vichier-Guerre, J. Iñaki Guijarro, Paola B. Arimondo, Chimie biologique épigénétique - Epigenetic Chemical Biology (EpiCBio), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Plateforme Technologique de RMN Biologique et HDX-MS - Biological NMR and HDX-MS Technological Platform, Institute of Chemistry for Life and Health Sciences (iCLeHS), Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), University of Stuttgart, The 800-MHz NMR spectrometer of the Institut Pasteur was partially funded by the Région Ile de France (SESAME 2014 NMRCHR grant no. 4014526). The project was financed by the French PPR Antiobioresistance ANR-20-PAMR-0011–TheraEPI (to P.B.A.)., We thank Prof. Srinivasan and Prof. Nelson from the Sidney Kimmel Comprehensive Cancer Center at the University of Medicine, Johns Hopkins (Baltimore, MD) for the kind gift of MBD2-His plasmid. We thank Ludovic Halby for the design of the synthetic pathway and for the fruitful discussions on the project conception., and ANR-20-PAMR-0011,TherAEPI,Thérapies épigénétiques pour esquiver la résistance(2020)
Subjects: DNA-Binding Proteins, 5-Methylcytosine, Humans, Molecular Medicine, CpG Islands, DNA, General Medicine, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, DNA Methylation, Biochemistry
Abstract: International audience; Epigenetics has received much attention in the past decade. Many insights on epigenetic (dys)regulation in diseases have been obtained, and clinical therapies targeting them are in place. However, the readers of the epigenetic marks are lacking enlightenment behind this revolution, and it is poorly understood how DNA methylation is being read and translated to chromatin function and cellular responses. Chemical probes targeting the methyl-CpG readers, such as the methyl-CpG binding domain proteins (MBDs), could be used to study this mechanism. We have designed analogues of 5-methylcytosine to probe the MBD domain of human MBD2. By setting up a protein thermal shift assay and an AlphaScreen-based test, we were able to identify three fragments that bind MBD2 alone and disrupt the MBD2-methylated DNA interactions. Two-dimensional NMR experiments and virtual docking gave valuable insights into the interaction of the ligands with the protein showing that the compounds interact with residues that are important for DNA recognition. These constitute the starting point for the design of potent chemical probes for MBD proteins.
Published: 2022

32. Variable oxygen environments and DNMT2 determine the DNA cytosine epigenetic landscape of Plasmodium falciparum

Author: Elie Hammam, Samia Miled, Frédéric Bonhomme, Benoit Arcangioli, Paola B. Arimondo, and Artur Scherf
Abstract: DNA cytosine methylation and its oxidized products are important epigenetic modifications in mammalian cells. Although 5-methylcytosine (5mC) was detected in the human malaria parasite Plasmodium falciparum, the presence of oxidized 5mC forms remain to be characterized. Here we establish a protocol to optimize nuclease-based DNA digestion for the extremely AT-rich genome of P. falciparum (>80% A+T) for quantitative LC-MS/MS analysis of 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC). We demonstrate the presence of 5hmC, 5fC and 5caC cytosine modifications in a DNMT2-only organism and observe striking ratio changes between 5mC and 5hmC during the 48-hour blood stage parasite development. Parasite-infected red blood cells cultured in different physiological oxygen concentrations revealed a shift in the cytosine modifications distribution towards the oxidized 5hmC and 5caC forms. In the absence of the canonical C5-DNA methyltransferase (DNMT1 and DNMT3A/B) in P. falciparum, we show that all cytosine modifications depend on the presence of DNMT2. We conclude that DNMT2 and oxygen levels are critical determinants that shape the dynamic cytosine epigenetic landscape in this human pathogen.
Published: 2021

33. Malaria Parasite Stress Tolerance Is Regulated by DNMT2-Mediated tRNA Cytosine Methylation

Author: Paola B. Arimondo, Frédéric Bonhomme, Benoit Arcangioli, Flore Nardella, Elie Hammam, Jiaqi Liang, Artur Scherf, Peter C. Dedon, Diane Erdmann, Peter R. Preiser, Sebastian Baumgarten, Ameya Sinha, Samia Miled, Biologie des Interactions Hôte-Parasite - Biology of Host-Parasite Interactions, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Singapore-MIT Alliance for Research and Technology (SMART), Massachusetts Institute of Technology (MIT), Nanyang Technological University [Singapour], Institut Jacques Monod (IJM (UMR_7592)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), École Technique Supérieure du Laboratoire [Paris] (ETSL), Chimie biologique épigénétique - Epigenetic Chemical Biology (EpiCBio), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Ecole doctorale Médicament -Toxicologie - Chimie - Imageries [Université de Paris] (ED 563), Université Paris Cité (UPCité), Dynamique du Génome - Dynamics of the genome, A. Sinha and J.L. acknowledge support from the Singapore‐MIT Alliance (SMA) Graduate Fellowship and MOE Tier 2 grant MOE2018-T2-2-131. Proteomics work was performed in part in the Center for Environmental Health Sciences BioCore, which is supported by Center grant P30‐ES002109 from the National Institute of Environmental Health Sciences. We also acknowledge Peiying Ho and Tan Tse Mien for providing support at SMART laboratories in Singapore. F.N. is supported by a Pasteur Cantarini fellowship. A. Sinha acknowledges financial support from the Singapore-MIT Alliance (SMA) Graduate Fellowships. P.B.A. acknowledges the DIM1Health 2019 grant from the Région Ile de France to the project EpiK for the LC/MS-MS equipment. This work was supported by the French Parasitology consortium ParaFrap (ANR-11-LABX0024) to A. Scherf, a Fondation Pasteur Swiss grant to A. Scherf, and an ANR grant (ANR-2019 EpiKillMal)., ANR-20-CE18-0006,EpiKillMal,Cibler la méthylation de l'ADN pour contrer la chimiorésistance du paludisme(2020), School of Biological Sciences, Singapore-MIT Alliance for Research and Technology, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Université de Paris (UP), Arimondo, Paola B, and Cibler la méthylation de l'ADN pour contrer la chimiorésistance du paludisme - - EpiKillMal2020 - ANR-20-CE18-0006 - AAPG2020 - VALID
Subjects: [SDV]Life Sciences [q-bio], Bisulfite sequencing, Protozoan Proteins, Epitranscriptomic, Epigenome, RNA, Transfer, homeostasis, Malaria, Falciparum, RNA Processing, Post-Transcriptional, Genetics, 0303 health sciences, biology, 030302 biochemistry & molecular biology, Biological sciences [Science], Translation (biology), epitranscriptomic, QR1-502, 3. Good health, [SDV] Life Sciences [q-bio], [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Codon usage bias, DNA methylation, RNA, Protozoan, Research Article, TRNA modification, Plasmodium falciparum, malaria, Microbiology, DNA methyltransferase, 03 medical and health sciences, Cytosine, Stress, Physiological, RNA cytosine methylation, Virology, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.MP] Life Sciences [q-bio]/Microbiology and Parasitology, tRNA, 030304 developmental biology, RNA, DNMT2, Methyltransferases, stress response, DNA Methylation, biology.organism_classification, Malaria, tRNA cytosine methylation, tRNA modification
Abstract: Malaria parasites need to cope with changing environmental conditions that require strong countermeasures to ensure pathogen survival in the human and mosquito hosts. The molecular mechanisms that protect Plasmodium falciparum homeostasis during the complex life cycle remain unknown. Here, we identify cytosine methylation of tRNAAsp (GTC) as being critical to maintain stable protein synthesis. Using conditional knockout (KO) of a member of the DNA methyltransferase family, called Pf-DNMT2, RNA bisulfite sequencing demonstrated the selective cytosine methylation of this enzyme of tRNAAsp (GTC) at position C38. Although no growth defect on parasite proliferation was observed, Pf-DNMT2KO parasites showed a selective downregulation of proteins with a GAC codon bias. This resulted in a significant shift in parasite metabolism, priming KO parasites for being more sensitive to various types of stress. Importantly, nutritional stress made tRNAAsp (GTC) sensitive to cleavage by an unknown nuclease and increased gametocyte production (>6-fold). Our study uncovers an epitranscriptomic mechanism that safeguards protein translation and homeostasis of sexual commitment in malaria parasites. IMPORTANCE P. falciparum is the most virulent malaria parasite species, accounting for the majority of the disease mortality and morbidity. Understanding how this pathogen is able to adapt to different cellular and environmental stressors during its complex life cycle is crucial in order to develop new strategies to tackle the disease. In this study, we identified the writer of a specific tRNA cytosine methylation site as a new layer of epitranscriptomic regulation in malaria parasites that regulates the translation of a subset of parasite proteins (>400) involved in different metabolic pathways. Our findings give insight into a novel molecular mechanism that regulates P. falciparum response to drug treatment and sexual commitment. Ministry of Education (MOE) Published version A. Sinha and J.L. acknowledge support from the Singapore‐MIT Alliance (SMA) Graduate Fellowship and MOE Tier 2 grant MOE2018-T2-2-131. Proteomics work was performed in part in the Center for Environmental Health Sciences BioCore, which is supported by Center grant P30‐ES002109 from the National Institute of Environmental Health Sciences. F.N. is supported by a Pasteur Cantarini fellowship. A. Sinha acknowledges financial support from the Singapore-MIT Alliance (SMA) Graduate Fellowships. P.B.A. acknowledges the DIM1Health 2019 grant from the Région Ile de France to the project EpiK for the LC/MS-MS equipment. This work was supported by the French Parasitology consortium ParaFrap (ANR-11-LABX0024) to A. Scherf, a Fondation Pasteur Swiss grant to A. Scherf, and an ANR grant (ANR-2019 EpiKillMal).
Published: 2021

34. The methylome of Biomphalaria glabrata and other mollusks: enduring modification of epigenetic landscape and phenotypic traits by a new DNA methylation inhibitor

Author: Koen J. F. Verhoeven, Slavica Ivanovic, Fleur Gawehns, Christoph Grunau, Patrice David, Nelia Luviano, Cristian Chaparro, Céline Cosseau, Paola B. Arimondo, Marie Lopez, Interactions Hôtes-Pathogènes-Environnements (IHPE), Université de Perpignan Via Domitia (UPVD)-Institut Français de Recherche pour l'Exploitation de la Mer (IFREMER)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche Pierre Fabre (Centre de R&D Pierre Fabre), PIERRE FABRE, Netherlands Institute of Ecology (NIOO-KNAW), Chimie biologique épigénétique - Epigenetic Chemical Biology (EpiCBio), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Centre d’Ecologie Fonctionnelle et Evolutive (CEFE), Université Paul-Valéry - Montpellier 3 (UPVM)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud])-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut Agro - Montpellier SupAgro, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), This work was supported by Wellcome Trust strategic award [107475/Z/15/Z] and by a PhD grant to NL from the Region Occitanie (EPIPARA project) and the University of Perpignan Via Domitia graduate school ED305. With the support of LabEx CeMEB, an ANR 'Investissements d’avenir' program (ANR-10-LABX-04-01) through the Environmental Epigenomics Platform and the 'projets de recherche exploratoires du CeMEB 2018' project 'Epigenetics of inbreeding depression (EPID)'. This study is set within the framework of the 'Laboratoires d'Excellences (LABEX)' TULIP (ANR‐10‐LABX‐41)., ANR-10-LABX-0004,CeMEB,Mediterranean Center for Environment and Biodiversity(2010), ANR-10-LABX-0041,TULIP,Towards a Unified theory of biotic Interactions: the roLe of environmental(2010), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Institut Français de Recherche pour l'Exploitation de la Mer (IFREMER)-Université de Perpignan Via Domitia (UPVD), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Pharmacochimie de la Régulation Epigénétique du Cancer (ETaC), PIERRE FABRE-Centre National de la Recherche Scientifique (CNRS), Netherlands Institute of Ecology - NIOO-KNAW (NETHERLANDS), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Royal Netherlands Academy of Arts and Sciences (KNAW), Université Paul-Valéry - Montpellier 3 (UPVM)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud])-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro), Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM), and Terrestrial Ecology (TE)
Subjects: [SDV]Life Sciences [q-bio], Bisulfite sequencing, DNA Methyltransferase Inhibitor, Locus (genetics), [CHIM.THER]Chemical Sciences/Medicinal Chemistry, QH426-470, Biology, Plan_S-Compliant-OA, Epigenesis, Genetic, Epigenome, chemistry.chemical_compound, 03 medical and health sciences, 0302 clinical medicine, Epigenetic inheritance, Genetics, Animals, Biomphalaria glabrata, Epimutation, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, 14. Life underwater, Epigenetics, Molecular Biology, [SDV.BDD]Life Sciences [q-bio]/Development Biology, 030304 developmental biology, 0303 health sciences, Mollusks, Biomphalaria, Research, [SDV.BID.EVO]Life Sciences [q-bio]/Biodiversity/Populations and Evolution [q-bio.PE], Phenotypic trait, Methylation, DNA Methylation, biology.organism_classification, Invertebrates, 5-Methylcytosine, DNMT inhibitors, chemistry, Mollusca, international, 030220 oncology & carcinogenesis, DNA methylation, 030217 neurology & neurosurgery
Abstract: Background 5-Methylcytosine (5mC) is an important epigenetic mark in eukaryotes. Little information about its role exists for invertebrates. To investigate the contribution of 5mC to phenotypic variation in invertebrates, alteration of methylation patterns needs to be produced. Here, we apply new non-nucleoside DNA methyltransferase inhibitors (DNMTi) to introduce aleatory changes into the methylome of mollusk species. Results Flavanone inhibitor Flv1 was efficient in reducing 5mC in the freshwater snails Biomphalaria glabrata and Physa acuta, and to a lesser degree, probably due to lower stability in sea water, in the oyster Crassostrea gigas. Flv1 has no toxic effects and significantly decreased the 5mC level in the treated B. glabrata and in its offspring. Drug treatment triggers significant variation in the shell height in both generations. A reduced representation bisulfite-sequencing method called epiGBS corroborates hypomethylation effect of Flv1 in both B. glabrata generations and identifies seven Differential Methylated Regions (DMR) out of 32 found both in Flv1-exposed snails and its progeny, from which 5 were hypomethylated, demonstrating a multigenerational effect. By targeted bisulfite sequencing, we confirmed hypomethylation in a locus and show that it is associated with reduced gene expression. Conclusions Flv1 is a new and efficient DNMTi that can be used to induce transient and heritable modifications of the epigenetic landscape and phenotypic traits in mollusks, a phylum of the invertebrates in which epigenetics is understudied.
Published: 2021

35. Synthesis and Biological Activity of a Cytostatic Inhibitor of MLLr Leukemia Targeting the DOT1L Protein

Author: Corinne Jallet, Yang Si, Veronique Cadet Daniel, Eva Levi-Acobas, Nemanja Djokovic, Katarina Nikolic, Paola B. Arimondo, Corentin Bon, Ludovic Halby, Melanie Pernak, Dusan Ruzic, Magdalena Barbachowska, Teodora Djikic, Chimie biologique épigénétique - Epigenetic Chemical Biology (EpiCBio), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Ecole doctorale Médicament -Toxicologie - Chimie - Imageries [Université de Paris] (ED 563), Université Paris Cité (UPCité), University of Belgrade [Belgrade], Région Ile de France supported the research with a Ph.D. fellowship to CB (ARDoC) and DIM OneHealth Investissements to PBA. Le Comité de Paris de la Ligue contre la Cancer (project Epi-Med 2020-2021) to PBA. Hubert Curien Partnership Project for collaboration France-Serbia 2020-2022 (Program Pavle Savic 2020) to PBA and KN. The authors collaborated in the frame of the EU COST CM1406 Epigenetic Chemical Biology program.D.R., N.D., T.D., K.N. acknowledge project of Ministry of Science and Technological Development of the Republic of Serbia, Faculty of Pharmacy, Contract No. 451-03-9/2021-14/200161., Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), and Université de Paris (UP)
Subjects: [SDV]Life Sciences [q-bio], Pharmaceutical Science, Drug design, Organic chemistry, bisubstrates, Methylation, Histone methylation, Article, Analytical Chemistry, Histones, 03 medical and health sciences, 0302 clinical medicine, QD241-441, Drug Discovery, medicine, Humans, Rational drug design, histone methylation, Physical and Theoretical Chemistry, MLL rearranged leukemia, 030304 developmental biology, 0303 health sciences, Leukemia, biology, Molecular Structure, Chemistry, HMT inhibitors, Biological activity, DOT1L, Histone-Lysine N-Methyltransferase, medicine.disease, Cytostatic Agents, 3. Good health, Histone, Chemistry (miscellaneous), 030220 oncology & carcinogenesis, Bisubstrates, DNA methylation, biology.protein, Cancer research, Molecular Medicine, rational drug design
Abstract: International audience; Histone methyltransferase DOT1L catalyzes mono-, di- and trimethylation of histone 3 at lysine residue 79 (H3K79) and hypermethylation of H3K79 has been linked to the development of acute leukemias characterized by the MLL (mixed-lineage leukemia) rearrangements (MLLr cells). The inhibition of H3K79 methylation inhibits MLLr cells proliferation, and an inhibitor specific for DOT1L, pinometostat, was in clinical trials (Phase Ib/II). However, the compound showed poor pharmacological properties. Thus, there is a need to find new potent inhibitors of DOT1L for the treatment of rearranged leukemias. Here we present the design, synthesis, and biological evaluation of a small molecule that inhibits in the nM level the enzymatic activity of hDOT1L, H3K79 methylation in MLLr cells with comparable potency to pinometostat, associated with improved metabolic stability and a characteristic cytostatic effect.
Published: 2021

36. Procainamide-SAHA fused inhibitors of hHDAC6 tackle multi-drug resistant malaria parasites

Author: Elie Hammam, Roger Peronet, Artur Scherf, Salah Mecheri, Camille Roesch, Ludovic Halby, Corentin Bon, Irina Dobrescu, Ambre Tafit, Paola B. Arimondo, Aurélie Claes, Diane Erdmann, Johanna Viluma, Véronique Cadet-Daniel, Melissa Mairet-Khedim, Benoit Witkowski, Flore Nardella, Biologie des Interactions Hôte-Parasite - Biology of Host-Parasite Interactions, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Chimie biologique épigénétique - Epigenetic Chemical Biology (EpiCBio), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Ecole doctorale Médicament -Toxicologie - Chimie - Imageries [Université de Paris] (ED 563), Université Paris Cité (UPCité), Malaria Molecular Epidemiology, Institut Pasteur du Cambodge, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), This work was supported by the Innovation program by Institut Pasteur-Institut Carnot (S-CR18089-02B15 DARRI CONSO INNOV 46-19, S-PI15006-10A INNOV 05-2019 ARIMONDO IARP 2019-PC), Pasteur Transversal Research Program (PTR 233-2019 HALBY), Pasteur Swiss Foundation grant, and ANR AAPG 2020-EpiKillMal, ANR-20-CE18-0006,EpiKillMal,Cibler la méthylation de l'ADN pour contrer la chimiorésistance du paludisme(2020), Nardella, Flore, Cibler la méthylation de l'ADN pour contrer la chimiorésistance du paludisme - - EpiKillMal2020 - ANR-20-CE18-0006 - AAPG2020 - VALID, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Université de Paris (UP), and Malaria Molecular Epidemiology (MMEU)
Subjects: medicine.medical_treatment, DNA Methyltransferase Inhibitor, Parasitemia, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, Pharmacology, Histone Deacetylase 6, Hydroxamic Acids, 01 natural sciences, HDAC6 inhibitors, Drug Discovery, Malaria, Falciparum, Cytotoxicity, 0303 health sciences, DNA methylation, antimalarial, Molecular Structure, biology, Chemistry, Drug Resistance, Multiple, 3. Good health, in vivo, [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, parasite, Molecular Medicine, [SDV.MP.PAR] Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, [CHIM.THER] Chemical Sciences/Medicinal Chemistry, Plasmodium falciparum, malaria, Dihydroartemisinin, Procainamide, Antimalarials, Structure-Activity Relationship, 03 medical and health sciences, parasitic diseases, medicine, Gametocyte, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, Histone deacetylase, 030304 developmental biology, drug resistance, Dose-Response Relationship, Drug, biology.organism_classification, medicine.disease, 0104 chemical sciences, Histone Deacetylase Inhibitors, Multiple drug resistance, 010404 medicinal & biomolecular chemistry, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Malaria
Abstract: International audience; Epigenetic post-translational modifications are essential for human malaria parasite survival and progression through its life cycle. Here, we present new functionalized suberoylanilide hydroxamic acid (SAHA) derivatives that chemically combine the pan-histone deacetylase inhibitor SAHA with the DNA methyltransferase inhibitor procainamide. A three- or four-step chemical synthesis was designed starting from cheap raw materials. Compared to the single drugs, the combined molecules showed a superior activity in Plasmodium and a potent inhibition against human HDAC6, exerting no cytotoxicity in human cell lines. These new compounds are fully active in multidrug-resistant Plasmodium falciparum Cambodian isolates. They target transmission of the parasite by inducing irreversible morphological changes in gametocytes and inhibiting exflagellation. The compounds are slow-acting and have an additive antimalarial effect in combination with fast-acting epidrugs and dihydroartemisinin. The lead compound decreases parasitemia in mice in a severe malaria model. Taken together, this novel fused molecule offers an affordable alternative to current failing antimalarial therapy.
Published: 2021

37. Towards the sustainable discovery and development of new antibiotics

Author: Ian H. Gilbert, Kenneth Pfarr, Timo Jaeger, Mika Lindvall, Anders Karlén, Philippe Glaser, Jennifer Herrmann, Marco Pieroni, Bertrand Aigle, Evi Stegmann, Heather Graz, Andrea Schiefer, Jean-Luc Pernodet, Thomas Hesterkamp, Rui Moreira, Heike Brötz-Oesterhelt, Andrew W. Truman, Andreas Keller, Ludovic Halby, Alexander Titz, José R. Tormo, Michael Graz, Kira J. Weissman, Olga Genilloud, Marc Stadler, Claus-Michael Lehr, Paola B. Arimondo, Mark Brönstrup, Savithri Ramurthy, Eriko Takano, Frédéric Peyrane, Mathias Winterhalter, Marnix H. Medema, Maarten van Dongen, Anna K. H. Hirsch, Achim Hoerauf, Helge B. Bode, Laurent Fraisse, Laura J. V. Piddock, Martin Empting, Brigitta Loretz, Yanyan Li, Heinz E. Moser, Tilmann Weber, Marcus Miethke, Silke Alt, Stefano Sabatini, Wolfgang Wohlleben, Peter Hammann, Stefano Donadio, Andriy Luzhetskyy, Myriam Seemann, Rolf Müller, Hrvoje Petković, Institut de Chimie de Strasbourg, Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Helmholtz-Zentrum für Infektionsforschung GmbH (HZI), Universität des Saarlandes [Saarbrücken], German Centre for Infection Research (DZIF), University of Parma = Università degli studi di Parma [Parme, Italie], Technical University of Denmark [Lyngby] (DTU), Justus-Liebig-Universität Gießen (JLU), Chimie biologique épigénétique - Epigenetic Chemical Biology (EpiCBio), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Ecologie et Evolution de la Résistance aux Antibiotiques / Ecology and Evolution of Antibiotics Resistance (EERA), Institut Pasteur [Paris]-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Dynamique des Génomes et Adaptation Microbienne (DynAMic), Université de Lorraine (UL)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Goethe-Universität Frankfurt am Main, Max Planck Institute for Terrestrial Microbiology, Max-Planck-Gesellschaft, Universidade de Lisboa (ULISBOA), Molécules de Communication et Adaptation des Micro-organismes (MCAM), Muséum national d'Histoire naturelle (MNHN)-Centre National de la Recherche Scientifique (CNRS), Wageningen University and Research [Wageningen] (WUR), Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Fundación MEDINA, John Innes Centre [Norwich], Ingénierie Moléculaire et Physiopathologie Articulaire (IMoPA), Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), University of Manchester [Manchester], Università degli Studi di Perugia (UNIPG), University of Tübingen, Jacobs University [Bremen], University Hospital Bonn, Biophys [Usk, UK], University of Bristol [Bristol], Recursion [Salt Lake City, UT], HiberCell [New York], Uppsala Universitet [Uppsala], AMR Insights, University of Ljubljana, BEAM Alliance, Naicons, Drugs for Neglected Diseases Initiative, Global Antibiotic Research and Development Partnership [Geneva, Switzerland] (GARDP), University of Dundee, Novartis Institutes for BioMedical Research (NIBR), The project on PqsR pathoblocker development acknowledges funding through the German Center for Infection Research (DZIF, projects TTU09.908 and TTU09.916), the Helmholtz Association (Helmholtz Validation Fund) and additional contributions by the associated academic institutes (HZI and HIPS). The development of chelocardins is supported by the DZIF (TTU09.814/09.821), the Helmholtz Innovation Fund (Pre-4D), by the Slovenian Research Agency, ARRS, grant no. J4-8226, and in collaboration with AciesBio, Slovenia. The corallopyronin project is funded by the DZIF (TTU09.807/09.816, TTU09.914), the German Federal Ministry of Education and Research (BMBF), the federal state of North Rhine-Westphalia (EFRE.NRW) and EU Horizon 2020. Eriko Takano was funded by the European Union’s Horizon 2020 research and innovation programme under grant agreement no. 720793 'TOPCAPI: Thoroughly Optimised Production Chassis for Advanced Pharmaceutical Ingredients'., European Project: 720793,H2020-EU.2.1.4.,TOPCAPI(2017), Università degli studi di Parma = University of Parma (UNIPR), Danmarks Tekniske Universitet = Technical University of Denmark (DTU), Justus-Liebig-Universität Gießen = Justus Liebig University (JLU), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Écologie et Évolution de la Résistance aux Antibiotiques / Ecology and Evolution of Antibiotics Resistance (EERA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Saclay-Université Paris Cité (UPCité)-Microbiologie Intégrative et Moléculaire (UMR6047), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Universidade de Lisboa = University of Lisbon (ULISBOA), Fundación MEDINA [Granada], Biotechnology and Biological Sciences Research Council (BBSRC), Università degli Studi di Perugia = University of Perugia (UNIPG), and Université de Strasbourg (UNISTRA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0303 health sciences, 030306 microbiology, Bioinformatics, General Chemical Engineering, [SDV]Life Sciences [q-bio], General Chemistry, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, Investment (macroeconomics), 3. Good health, 03 medical and health sciences, Roadmap, Risk analysis (engineering), 13. Climate action, Order (exchange), Blueprint, ddc:570, Business strategy in drug development, Bioinformatica, Life Science, ddc:610, Business, Drug therapy, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology
Abstract: An ever-increasing demand for novel antimicrobials to treat life-threatening infections caused by the global spread of multidrug-resistant bacterial pathogens stands in stark contrast to the current level of investment in their development, particularly in the fields of natural-product-derived and synthetic small molecules. New agents displaying innovative chemistry and modes of action are desperately needed worldwide to tackle the public health menace posed by antimicrobial resistance. Here, our consortium presents a strategic blueprint to substantially improve our ability to discover and develop new antibiotics. We propose both short-term and long-term solutions to overcome the most urgent limitations in the various sectors of research and funding, aiming to bridge the gap between academic, industrial and political stakeholders, and to unite interdisciplinary expertise in order to efficiently fuel the translational pipeline for the benefit of future generations., Antimicrobial resistance is an increasing threat to public health and encouraging the development of new antimicrobials is one of the most important ways to address the problem. This Roadmap article aims to bring together industrial, academic and political partners, and proposes both short-term and long-term solutions to this challenge.
Published: 2021

38. DNA Methylation Targeting: The DNMT/HMT Crosstalk Challenge

Author: Omar Castillo-Aguilera, Patrick Depreux, Ludovic Halby, Paola B. Arimondo, and Laurence Goossens
Subjects: DNA methylation, histone methylation, DNMT/HMT crosstalk, DNMT inhibitors, HMT inhibitors, Microbiology, QR1-502
Abstract: Chromatin can adopt a decondensed state linked to gene transcription (euchromatin) and a condensed state linked to transcriptional repression (heterochromatin). These states are controlled by epigenetic modulators that are active on either the DNA or the histones and are tightly associated to each other. Methylation of both DNA and histones is involved in either the activation or silencing of genes and their crosstalk. Since DNA/histone methylation patterns are altered in cancers, molecules that target these modifications are interesting therapeutic tools. We present herein a vast panel of DNA methyltransferase inhibitors classified according to their mechanism, as well as selected histone methyltransferase inhibitors sharing a common mode of action.
Published: 2017
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39. Properly substituted analogues of BIX-01294 lose inhibition of G9a histone methyltransferase and gain selective anti-DNA methyltransferase 3A activity.

Author: Dante Rotili, Domenico Tarantino, Biagina Marrocco, Christina Gros, Véronique Masson, Valérie Poughon, Fréderic Ausseil, Yanqi Chang, Donatella Labella, Sandro Cosconati, Salvatore Di Maro, Ettore Novellino, Michael Schnekenburger, Cindy Grandjenette, Celine Bouvy, Marc Diederich, Xiaodong Cheng, Paola B Arimondo, and Antonello Mai
Subjects: Medicine, Science
Abstract: Chemical manipulations performed on the histone H3 lysine 9 methyltransferases (G9a/GLP) inhibitor BIX-01294 afforded novel desmethoxyquinazolines able to inhibit the DNA methyltransferase DNMT3A at low micromolar levels without any significant inhibition of DNMT1 and G9a. In KG-1 cells such compounds, when tested at sub-toxic doses, induced the luciferase re-expression in a stable construct controlled by a cytomegalovirus (CMV) promoter silenced by methylation (CMV-luc assay). Finally, in human lymphoma U-937 and RAJI cells, the N-(1-benzylpiperidin-4-yl)-2-(4-phenylpiperazin-1-yl)quinazolin-4-amine induced the highest proliferation arrest and cell death induction starting from 10 µM, in agreement with its DNMT3A inhibitory potency.
Published: 2014
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40. A novel screening strategy to identify histone methyltransferase inhibitors reveals a crosstalk between DOT1L and CARM1

Author: Yang Si, Corentin Bon, Magdalena Barbachowska, Veronique Cadet-Daniel, Corinne Jallet, Laura Soresinetti, Mikaël Boullé, Magalie Duchateau, Mariette Matondo, Fabrice Agou, Ludovic Halby, Paola B. Arimondo, Chimie biologique épigénétique - Epigenetic Chemical Biology (EpiCBio), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Ecole doctorale Médicament -Toxicologie - Chimie - Imageries [Université de Paris] (ED 563), Université Paris Cité (UPCité), Criblage chémogénomique et biologique (Plateforme) - Chemogenomic and Biological Screening Platform (PF-CCB), Institut Pasteur [Paris] (IP), Plateforme de Protéomique / Proteomics platform, Spectrométrie de Masse pour la Biologie – Mass Spectrometry for Biology (UTechS MSBio), Institut Pasteur [Paris] (IP)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris] (IP)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), We thank the 'Region Ile de France' for the financing of the PhD of Mr Bon (ArDOC fellowship) and Ligue national contre le Cancer, comité de Paris (grants RS20/75-82 and RS21/75-31 to PBA). This work benefited from a government grant (PPR Antibioresistance) managed by the Agence Nationale de la Recherche – Programme d'Investissements d'Avenir (ANR-20-PAMR-0011)., and ANR-20-PAMR-0011,TherAEPI,Thérapies épigénétiques pour esquiver la résistance(2020)
Subjects: Chemistry (miscellaneous), [SDV]Life Sciences [q-bio], Biochemistry, Genetics and Molecular Biology (miscellaneous), Molecular Biology, Biochemistry
Abstract: International audience; Epigenetic regulation is a dynamic and reversible process that controls gene expression. Abnormal function results in human diseases such as cancer, thus the enzymes that establish epigenetic marks, such as histone methyltransferases (HMTs), are potentially therapeutic targets. Noteworthily, HMTs form multiprotein complexes that in concert regulate gene expression. To probe epigenetic protein complexes regulation in cells, we developed a reliable chemical biology high-content imaging strategy to screen compound libraries simultaneously on multiple histone marks inside cells. By this approach, we identified that compound 4, a published CARM1 inhibitor, inhibits both histone mark H3R2me2a, regulated also by CARM1, and H3K79me2, regulated only by DOT1L, pointing out a crosstalk between CARM1 and DOT1L. Based on this interaction, we combined compound 4 and DOT1L inhibitor EPZ-5676 resulting in a stronger inhibition of cell proliferation and increase in apoptosis, indicating that our approach identifies possible effective synergistic drug combinations.
Published: 2021

41. Targeting Germ Cell Tumors with the Newly Synthesized Flavanone-Derived Compound MLo1302 Efficiently Reduces Tumor Cell Viability and Induces Apoptosis and Cell Cycle Arrest

Author: Rui Henrique, Leendert H. J. Looijenga, Paola B. Arimondo, Marie Lopez, João Lobo, Vera Miranda-Gonçalves, Ana Rita Cardoso, Carmen Jerónimo, Instituto Português de Oncologia do Porto / Portuguese Oncology Institute of Porto (IPO Porto), Universidade do Porto, Princess Máxima Center for Pediatric Oncology [Utrecht, Netherlands], Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Chimie biologique épigénétique - Epigenetic Chemical Biology (EpiCBio), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), This work was supported by Programa Operacional Competitividade e Internacionalização (POCI), in the component FEDER, and by national funds (OE) through FCT/MCTES, in the scope of the project EpiMarkGermCell (PTDC/MECONC/29043/2017). JL is recipient of a fellowship from FCT-Fundação para a Ciência e Tecnologia—(SFRH/BD/132751/2017). VM-G contract is funded by POCI-01-0145-FEDER-29043., Authors would like to acknowledge Daniel Nettersheim, Christoph Oing and Friedemann Honecker for sharing the NCCIT-R cell line., Universidade do Porto = University of Porto, and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Cell cycle checkpoint, drug design, Cellular differentiation, [SDV]Life Sciences [q-bio], Caspase 2, Testicular Germ Cell Tumor, Pharmaceutical Science, Decitabine, lcsh:RS1-441, Caspase 8, Article, lcsh:Pharmacy and materia medica, 03 medical and health sciences, 0302 clinical medicine, medicine, [CHIM]Chemical Sciences, Viability assay, epidrugs, 030304 developmental biology, 0303 health sciences, DNA methylation, biology, Chemistry, 3. Good health, cell differentiation, Apoptosis, 030220 oncology & carcinogenesis, biology.protein, Cancer research, testicular germ cell tumors, medicine.drug
Abstract: International audience; Less toxic treatment strategies for testicular germ cell tumor (TGCT) patients are needed, as overtreatment is a concern due to the long-term side effects of platin-based chemotherapy. Although clinical benefit from classical hypomethylating agents has to date been limited, TGCTs show an abnormal DNA methylome indicating the potential of treating TGCTs with hypomethylating drugs. We tested, for the first time in TGCT cell lines, a new synthetic flavonoid compound (MLo1302) from the 3-nitroflavanone family of DNA methyltransferase (DNMT) inhibitors. We show that MLo1302 reduces cell viability (including of cisplatin resistant cell line NCCIT-R), with IC50s (inhibitory concentration 50) within the nanomolar range for NCCIT and NTERA-2 cells, and proved its cytotoxic effect. Exposure to MLo1302 reduced DNMT protein expression, similar to decitabine, and showed a partial effect in cell differentiation, reducing protein expression of pluripotency markers. RT2 profiler expression array indicated several dysregulated targets, related to activation of apoptosis, differentiation, and cell cycle arrest. We validated these data by showing increased apoptosis, increased protein expression of cleaved caspase 8 and activated caspase 2, and reduced proliferation (BrdU assay), with increase in CDKN1A and decrease in MIB-1 expression. Therefore, synthetic drugs designed to target DNA methylation in cells may uncover effective treatments for TGCT patients
Published: 2021

42. Study of the Effect of Substituents of ortho-Phenylenediamines in the Opening of Lactones and Lactams for Access to Benzimidazol-2-yl Alkanols and Benzimidazol-2-yl Alkylamines

Author: Florian Beaurain, Patrick Depreux, Laurence Goossens, Omar Castillo-Aguilera, Alexia Ballée, Paola B. Arimondo, Groupe de Recherche sur les formes Injectables et les Technologies Associées - ULR 7365 (GRITA), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institut de Chimie Pharmaceutique Albert Lespagnol (ICPAL), Université de Lille, Droit et Santé, Chimie biologique épigénétique - Epigenetic Chemical Biology (EpiCBio), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), This work was supported by the Centre National de la Recherche Scientifique (CNRS) and PlanCancer 2014 (N° EPIG201401) (to P.B.A), and by a PhD fellowship by the Ecole Doctorale Biologie Santé de Lille (EDBSL, France) National Council of Science and Technology (Consejo Nacional de Ciencia y Tecnología, CONACYT, Mexico) (to O.C.A.)., and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)
Subjects: chemistry.chemical_classification, 2-benzimidazol-2-yl alkylamines, 010405 organic chemistry, Chemistry, Carboxylic acid, [SDV]Life Sciences [q-bio], Organic Chemistry, Condensation, 010402 general chemistry, 01 natural sciences, Medicinal chemistry, 3. Good health, 0104 chemical sciences, lactones, chemistry.chemical_compound, ortho-phenylenediamines, Yield (chemistry), [CHIM]Chemical Sciences, lactams, Derivative (chemistry), 2-benzimidazol-2-yl alkanols
Abstract: International audience; Benzimidazoles represent common chemical moieties in bioactive compounds. The synthesis of this heterocycle often involves a condensation of an ortho-phenylenediamine with a carboxylic acid derivative. The observed dialkylation of the starting ortho-phenylenediamine is avoided by opening of lactones or lactams. This strategy can directly yield 1H-benzimidazoles substituted at the 2-position by a functionalized chain. We present herein a study of the effect of different electron-withdrawing or electron-donating groups at the 4-position of ortho-phenylenediamines on the opening of lactones or lactams to synthesize benzimidazol-2-yl alkanols and benzimidazol-2-yl alkylamines.
Published: 2020

43. Bisubstrate-Type Chemical Probes Identify GRP94 as a Potential Target of Cytosine-Containing Adenosine Analogs

Author: Gabriela Chiosis, Marie Lopez, Odile Burlet-Schiltz, Fanny Assemat, Pengrong Yan, Dany Pechalrieu, Ludovic Halby, Sahil Sharma, Karima Chaoui, Marlène Marcellin, Paola B. Arimondo, Pharmacochimie de la Régulation Epigénétique du Cancer (ETaC), PIERRE FABRE-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Chimie biologique épigénétique - Epigenetic Chemical Biology (EpiCBio), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Institut de pharmacologie et de biologie structurale (IPBS), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Memorial Sloane Kettering Cancer Center [New York], Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), This work was supported by PlanCancer2014 France (no. EPIG201401), the Centre National pour la Recherche Scientifique (CNRS), the research center Pierre Fabre, the Région Occitanie, Toulouse Métropole, FEDER (Fonds Européens de Développement Régional) and the French Ministry of Research (Programme Investissement d’Avenir, Infrastructures Nationales en Biologie et Santé, Proteomics French Infrastructure project, ANR 10-INBS-08). This work was also funded in part by P01 CA186866 and P30 CA008748 (NCI Core Facility Grant)., ANR-10-INBS-0008,ProFI,Infrastructure Française de Protéomique(2010), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Université Toulouse III - Paul Sabatier (UT3), and Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Proteomics, 0301 basic medicine, Adenosine, Proteome, Ultraviolet Rays, [SDV]Life Sciences [q-bio], Drug target, Chemical probe, 01 natural sciences, Biochemistry, Article, Cytosine, 03 medical and health sciences, chemistry.chemical_compound, Cell Line, Tumor, medicine, Humans, [CHIM]Chemical Sciences, Membrane Glycoproteins, 010405 organic chemistry, Chemistry, Extramural, Affinity Labels, General Medicine, 0104 chemical sciences, 3. Good health, 030104 developmental biology, Click chemistry, Molecular Medicine, Click Chemistry, medicine.drug
Abstract: International audience; We synthesized affinity-based chemical probes of cytosine-adenosine bisubstrate analogs and identified several potential targets by proteomic analysis. The validation of the proteomic analysis identified the chemical probe as a specific inhibitor of glucose-regulated protein 94 (GRP94), a potential drug target for several types of cancers. Therefore, as a result of the use of bisubstrate-type chemical probes and a chemical-biology methodology, this work opens the way to the development of a new family of GRP94 inhibitors that could potentially be of therapeutic interest.
Published: 2020

44. Contributors

Author: Hélder Almeida-Lousada, Lucia Altucci, Paola B. Arimondo, Alexandra Binnie, Corentin Bon, Ramon Cacabelos, Vânia Camilo, Pedro Castelo-Branco, Claudia C. dos Santos, Marta Dueñas, Ahmed El-Serafi, Ibrahim El-Serafi, Bradley S. Ferguson, Mónica T. Fernandes, Panagis Filippakopoulos, Francesco Fiorentino, A. Ganesan, Aleksander M. Grabiec, Justine S. Habibian, Elizabeth Henderson, Rui Henrique, Georges Herbein, Carmen Jerónimo, Haroon Khan, Katarzyna B. Lagosz, João Lobo, Antonello Mai, Olaia Martínez-Iglesias, Ester Munera-Maravilla, Angela Nebbioso, Zeina Nehme, Jesús M. Paramio, Sébastien Pasquereau, Jacob Peedicayil, Anju M. Philip, Dante Rotili, Federica Sarno, Yang Si, and Hammad Ullah
Published: 2020

45. Targeting DOT1L for mixed-lineage rearranged leukemia

Author: Yang Si, Paola B. Arimondo, Corentin Bon, Chimie biologique épigénétique - Epigenetic Chemical Biology (EpiCBio), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Ecole doctorale Médicament -Toxicologie - Chimie - Imageries [Université de Paris] (ED 563), Université de Paris (UP), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), and Université Paris Cité (UPCité)
Subjects: MLL, assay development, Arginine, Lysine, Computational biology, Biology, 03 medical and health sciences, 0302 clinical medicine, hemic and lymphatic diseases, medicine, [CHIM]Chemical Sciences, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, histone methylation, MLL leukemia, 030304 developmental biology, 0303 health sciences, Acute leukemia, Inhibitors, DOT1L, Methylation, medicine.disease, 3. Good health, Leukemia, Histone, 030220 oncology & carcinogenesis, Histone methyltransferase, biology.protein
Abstract: International audience; Histone methyltransferases are potential therapeutic targets for human diseases, in particular cancer. Among them, DOT1L is a lysine histone methyltransferase (KHMT) that catalyzes the methylation of lysine 79 on histone 3. Structurally, its catalytic domain is distinguished by the presence of a seven-stranded β-sheet motif, common to arginine histone methyltransferases, making it a unique KHMT. In addition to this unicity, which makes it a very interesting therapeutic target from a medicinal chemistry point of view, DOT1L plays a major role in mixed-lineage rearranged leukemia, an important subset of acute leukemia with very poor overall survival rate. Here, after an introduction to DOT1L and its role in MLL-r leukemia, we discuss the development of DOT1L inhibitors for the treatment of MLL-r and the assays used to discover and evaluate the inhibitors.
Published: 2020

46. Novel quinoline compounds active in cancer cells through coupled DNA methyltransferase inhibition and degradation

Author: Clemens Zwergel, Marco Tripodi, Donatella Del Bufalo, Annalisa Romanelli, Daniela Trisciuoglio, Cecilia Battistelli, Lucia Altucci, Giulia Stazi, Paola B. Arimondo, Rossella Fioravanti, Teresa De Luca, Alexandra Paulo, Dany Pechalrieu, Sergio Valente, Raffaele Strippoli, Angela Nebbioso, Federica Sarno, Eduarda Mendes, Antonello Mai, Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA), Università degli studi della Campania 'Luigi Vanvitelli' = University of the Study of Campania Luigi Vanvitelli, Universidade de Lisboa = University of Lisbon (ULISBOA), Istituto Nazionale di Malattie Infettive 'Lazzaro Spallanzani' (INMI), Department of Molecular Medicine, Institut Pasteur, Fondation Cenci Bolognetti - Istituto Pasteur Italia, Fondazione Cenci Bolognetti, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA), Pharmacochimie de la Régulation Epigénétique du Cancer (ETaC), PIERRE FABRE-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Chimie biologique épigénétique - Epigenetic Chemical Biology (EpiCBio), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), IFO - Istituto Nazionale Tumori Regina Elena [Roma] (IRE), CNR Istituto di Biologia e Patologia Molecolari [Roma] (CNR | IBPM), National Research Council of Italy | Consiglio Nazionale delle Ricerche (CNR), This work was supported by PRIN 2016 (prot. 20152TE5PK) (L.A., A.M.), Ricerca Finalizzata 2013 PE-2013-02355271 (A.M.), the Italian Association for Cancer Research AIRC-19162 (A.M.), AIRC-17217 (L.A.) and AIRC-18560 (D.D.B.), NIH (n. R01GM114306) (A.M.), VALERE: Vanvitelli per la Ricerca Program (L.A.), FP7-BLUEPRINT (282510) (L.A., A.M.), the Campania Regional Government Lotta alle Patologie Oncologiche (L.A.), iCURE (CUP B21c17000030007) (L.A.), Campania Regional Government FASE 2: IDEAL (CUP B63D18000560007) (L.A.), PlanCancer2014 (P.B.A.) and FCT, Portugal through UID/DTP/04138/2019 (A.P., E.M.) funds., Zwergel, C., Fioravanti, R., Stazi, G., Sarno, F., Battistelli, C., Romanelli, A., Nebbioso, A., Mendes, E., Paulo, A., Strippoli, R., Tripodi, M., Pechalrieu, D., Arimondo, P. B., De Luca, T., Del Bufalo, D., Trisciuoglio, D., Altucci, L., Valente, S., Mai, A., Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], Università degli studi della Campania 'Luigi Vanvitelli', Universidade de Lisboa (ULISBOA), Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome]-Institut Pasteur, Fondation Cenci Bolognetti - Istituto Pasteur Italia, Fondazione Cenci Bolognetti, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Institute of Molecular Pathology and Biology [Rome] (IPBM), and Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome]-Consiglio Nazionale delle Ricerche (CNR)
Subjects: 0301 basic medicine, Cancer Research, Methyltransferase, [SDV]Life Sciences [q-bio], Azacitidine, Decitabine, DNA methyltransferase, Apoptosis, Medicinal chemistry, Protein degradation, lcsh:RC254-282, Article, 03 medical and health sciences, 0302 clinical medicine, medicine, [CHIM]Chemical Sciences, Chemistry, Drug discovery, Apoptosi, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, 3. Good health, Enzyme inhibition, 030104 developmental biology, Oncology, Cell culture, 030220 oncology & carcinogenesis, Cancer cell, Cancer research, DNMT1, medicine.drug
Abstract: DNA methyltransferases (DNMTs) play a relevant role in epigenetic control of cancer cell survival and proliferation. Since only two DNMT inhibitors (azacitidine and decitabine) have been approved to date for the treatment of hematological malignancies, the development of novel potent and specific inhibitors is urgent. Here we describe the design, synthesis, and biological evaluation of a new series of compounds acting at the same time as DNMTs (mainly DNMT3A) inhibitors and degraders. Tested against leukemic and solid cancer cell lines, 2a&ndash, c and 4a&ndash, c (the last only for leukemias) displayed up to submicromolar antiproliferative activities. In HCT116 cells, such compounds induced EGFP gene expression in a promoter demethylation assay, confirming their demethylating activity in cells. In the same cell line, 2b and 4c chosen as representative samples induced DNMT1 and -3A protein degradation, suggesting for these compounds a double mechanism of DNMT3A inhibition and DNMT protein degradation.
Published: 2020
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47. Demethylation by low-dose 5-aza-2′-deoxycytidine impairs 3D melanoma invasion partially through miR-199a-3p expression revealing the role of this miR in melanoma

Author: Chantal Etievant, Audrey Delmas, Paola B. Arimondo, Arnaud Pillon, Gilles Favre, Joëlle Riond, Jörg Tost, Arnaud Carrier, Florence Busato, Cécile Desjobert, Antoine Daunay, Diego M. Marzese, Pharmacochimie de la Régulation Epigénétique du Cancer (ETaC), PIERRE FABRE-Centre National de la Recherche Scientifique (CNRS), Centre de biologie du développement (CBD), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Centre d'Etude du Polymorphisme Humain (CEPH), Université Paris Diderot - Paris 7 (UPD7)-Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Fondation Jean Dausset, Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Laboratoires Pierre Fabre, Laboratoire d'Epigénétique et d'Environnement [Evry] (CNG - CEA), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de Genotypage-Institut de Génomique [Evry], Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS), PIERRE FABRE-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Centre de Biologie Intégrative (CBI), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), John Wayne Cancer Institute [Santa Monica, CA, USA], Chimie biologique épigénétique - Epigenetic Chemical Biology (EpiCBio), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), This work was supported to P.B.A. by Centre National de la Recherche Scientifique (CNRS) [ATIP], Région Midi Pyrenées [Equipe d’Excellence and FEDER CNRS/Région Midi Pyrenées], Fondation InNaBioSanté, and PlanCancer2014 (N°EPIG201401)., Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre de Biologie Intégrative (CBI), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Fondation Jean Dausset-Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Centre de Biologie Intégrative (CBI), and Riond, Joelle
Subjects: 0301 basic medicine, Lung Neoplasms, [SDV]Life Sciences [q-bio], lcsh:Medicine, MESH: Spheroids, Cellular, Transcriptome, Mice, chemistry.chemical_compound, 0302 clinical medicine, MESH: DNA Methylation, MESH: Up-Regulation, MESH: Sequence Analysis, RNA, Gene Regulatory Networks, MESH: Animals, Promoter Regions, Genetic, Melanoma, Genetics (clinical), MESH: Gene Regulatory Networks, DNA methylation, microRNA, MESH: Gene Expression Regulation, Neoplastic, Up-Regulation, 3. Good health, Gene Expression Regulation, Neoplastic, [SDV] Life Sciences [q-bio], MESH: Cell Survival, 030220 oncology & carcinogenesis, Female, Deoxycytidine, Epigenetics, MESH: Cell Line, Tumor, lcsh:QH426-470, Cell Survival, MESH: Melanoma, education, Biology, Decitabine, 03 medical and health sciences, MESH: Gene Expression Profiling, In vivo, Cell Line, Tumor, Spheroids, Cellular, MESH: Promoter Regions, Genetic, Genetics, medicine, Animals, Humans, Neoplasm Invasiveness, Molecular Biology, MESH: Mice, neoplasms, MESH: Humans, MESH: Decitabine, Sequence Analysis, RNA, Research, Gene Expression Profiling, lcsh:R, MESH: Neoplasm Invasiveness, medicine.disease, Demethylating agent, MESH: Lung Neoplasms, lcsh:Genetics, MicroRNAs, 030104 developmental biology, chemistry, Cancer research, Melanoma aggressiveness, MESH: Female, MESH: MicroRNAs, Neoplasm Transplantation, MESH: Neoplasm Transplantation, Developmental Biology
Abstract: Background Efficient treatments against metastatic melanoma dissemination are still lacking. Here, we report that low-cytotoxic concentrations of 5-aza-2′-deoxycytidine, a DNA demethylating agent, prevent in vitro 3D invasiveness of metastatic melanoma cells and reduce lung metastasis formation in vivo. Results We unravelled that this beneficial effect is in part due to MIR-199A2 re-expression by promoter demethylation. Alone, this miR showed an anti-invasive and anti-metastatic effect. Throughout integration of micro-RNA target prediction databases with transcriptomic analysis after 5-aza-2′-deoxycytidine treatments, we found that miR-199a-3p downregulates set of genes significantly involved in invasion/migration processes. In addition, analysis of data from melanoma patients showed a stage- and tissue type-dependent modulation of MIR-199A2 expression by DNA methylation. Conclusions Thus, our data suggest that epigenetic- and/or miR-based therapeutic strategies can be relevant to limit metastatic dissemination of melanoma. Electronic supplementary material The online version of this article (10.1186/s13148-018-0600-2) contains supplementary material, which is available to authorized users.
Published: 2019

48. DNA Methylation Bisubstrate Inhibitors Are Fast-Acting Drugs Active against Artemisinin-Resistant Plasmodium falciparum Parasites

Author: Salah Mecheri, Benoit Witkowski, Flore Nardella, Artur Scherf, Elie Hammam, Ludovic Halby, Roger Peronet, Didier Menard, Véronique Cadet-Daniel, Diane Erdmann, Paola B. Arimondo, Biologie des Interactions Hôte-Parasite - Biology of Host-Parasite Interactions, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Chimie biologique épigénétique - Epigenetic Chemical Biology, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), ED 515 - Complexité du vivant, Sorbonne Université (SU), Malaria Molecular Epidemiology, Institut Pasteur du Cambodge, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), This work was supported by a European Research Council Advanced Grant (PlasmoSilencing 670301), a Fondation Pasteur Swiss grant and the French Parasitology consortium ParaFrap (ANR-11-LABX0024) to A.S., as well as DARRI Carnot Pasteur MS 2019 Projet INNOV-5-19 to A.S. and P.B.A., DIM1 Health Ile de France 2019 to P.B.A., and PTR Institut Pasteur 2019 (TaME) to L.H. and F.N, We thank Dr. T. Ishino (Department of Medical Zoology, Mie University School of Medicine, Edobashi, Tsu, Japan) for her kind gift of the P. berghei ANKA GFP-expressing strain.(26) We thank Agnès Zettor and Fabrice Agou of the PF-CCB (Institut Pasteur) for the solubility analysis and Eric Legrand (Biology of Host-Parasite Interactions, Institut Pasteur, Paris) for his technical assistance., ANR-11-LABX-0024/11-LABX-0024,ParaFrap,Alliance française contre les maladies parasitaires(2011), European Project: 670301,H2020,ERC-2014-ADG,PlasmoSilencing(2015), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Chimie biologique épigénétique - Epigenetic Chemical Biology (EpiCBio), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Ecole Doctorale Complexité du Vivant (ED515), Université Paris Cité (UPCité), Réseau International des Instituts Pasteur (RIIP), ANR-11-LABX-0024,ParaFrap,Alliance française contre les maladies parasitaires(2011), MECHERI, Salah, Laboratoires d'excellence - Alliance française contre les maladies parasitaires - - ParaFrap2011 - ANR-11-LABX-0024 - LABX - VALID, Exoribonuclease-mediated degradation of nascent RNA in Malaria Parasites: A Novel Mechanism in Virulence Gene Silencing - PlasmoSilencing - - H20202015-11-01 - 2020-10-31 - 670301 - VALID, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), and Université de Paris (UP)
Subjects: Artemisinins, General Chemical Engineering, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, 010402 general chemistry, 01 natural sciences, Plasmodium, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, [SDV.IMM.VAC] Life Sciences [q-bio]/Immunology/Vaccinology, In vivo, parasitic diseases, medicine, [CHIM]Chemical Sciences, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, Artemisinin, [SDV.IMM.ALL]Life Sciences [q-bio]/Immunology/Allergology, [SDV.IMM.II] Life Sciences [q-bio]/Immunology/Innate immunity, QD1-999, biology, 010405 organic chemistry, Plasmodium falciparum, General Chemistry, medicine.disease, biology.organism_classification, Virology, 0104 chemical sciences, 3. Good health, Chemistry, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, [SDV.IMM.IA] Life Sciences [q-bio]/Immunology/Adaptive immunology, Parasitic disease, DNA methylation, [SDV.IMM.VAC]Life Sciences [q-bio]/Immunology/Vaccinology, [SDV.IMM.ALL] Life Sciences [q-bio]/Immunology/Allergology, [SDV.MP.PAR] Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, Malaria, Research Article, medicine.drug
Abstract: Malaria is the deadliest parasitic disease affecting over 200 million people worldwide. The increasing number of treatment failures due to multi-drug-resistant parasites in South-East Asia hinders the efforts for elimination. It is thus urgent to develop new antimalarials to contain these resistant parasites. Based on a previous report showing the presence of DNA methylation in Plasmodium, we generated new types of DNA methylation inhibitors against malaria parasites. The quinoline–quinazoline-based inhibitors kill parasites, including artemisinin-resistant field isolates adapted to culture, in the low nanomolar range. The compounds target all stages of the asexual cycle, including early rings, during a 6 h treatment period; they reduce DNA methylation in the parasite and show in vivo activity at 10 mg/kg. These potent inhibitors are a new starting point to develop fast-acting antimalarials that could be used in combination with artemisinins., Bisubstrate inhibitors of DNA methylation efficiently kill malaria parasites, including artemisinin-resistant ones. They act in 6 h during all stages of the asexual cycle and show in vivo activity.
Published: 2019

49. Replication-fork stalling and processing at a single psoralen interstrand crosslink in Xenopus egg extracts.

Author: Cyrille Le Breton, Magali Hennion, Paola B Arimondo, and Olivier Hyrien
Subjects: Medicine, Science
Abstract: Interstrand crosslink (ICL)-inducing agents block the separation of the two DNA strands. They prevent transcription and replication and are used in clinics for the treatment of cancer and skin diseases. Here, we have introduced a single psoralen ICL at a specific site in plasmid DNA using a triplex-forming-oligonucleotide (TFO)-psoralen conjugate and studied its repair in Xenopus egg extracts that support nuclear assembly and replication of plasmid DNA. Replication forks arriving from either side stalled at the psoralen ICL. In contrast to previous observations with other ICL-inducing agents, the leading strands advanced up to the lesion without any prior pausing. Subsequently, incisions were introduced on one parental strand on both sides of the ICL. These incisions could be detected whether one or both forks reached the ICL. Using small molecule inhibitors, we found that the ATR-Chk1 pathway, but not the ATM-Chk2 pathway, stimulated both the incision step and the subsequent processing of the broken replication intermediates. Our results highlight both similarities and differences in fork stalling and repair induced by psoralen and by other ICL-forming agents.
Published: 2011
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50. Mechanistic insights on the inhibition of c5 DNA methyltransferases by zebularine.

Author: Christine Champion, Dominique Guianvarc'h, Catherine Sénamaud-Beaufort, Renata Z Jurkowska, Albert Jeltsch, Loïc Ponger, Paola B Arimondo, and Anne-Laure Guieysse-Peugeot
Subjects: Medicine, Science
Abstract: In mammals DNA methylation occurs at position 5 of cytosine in a CpG context and regulates gene expression. It plays an important role in diseases and inhibitors of DNA methyltransferases (DNMTs)--the enzymes responsible for DNA methylation--are used in clinics for cancer therapy. The most potent inhibitors are 5-azacytidine and 5-azadeoxycytidine. Zebularine (1-(beta-D-ribofuranosyl)-2(1H)- pyrimidinone) is another cytidine analog described as a potent inhibitor that acts by forming a covalent complex with DNMT when incorporated into DNA. Here we bring additional experiments to explain its mechanism of action. First, we observe an increase in the DNA binding when zebularine is incorporated into the DNA, compared to deoxycytidine and 5-fluorodeoxycytidine, together with a strong decrease in the dissociation rate. Second, we show by denaturing gel analysis that the intermediate covalent complex between the enzyme and the DNA is reversible, differing thus from 5-fluorodeoxycytidine. Third, no methylation reaction occurs when zebularine is present in the DNA. We confirm that zebularine exerts its demethylation activity by stabilizing the binding of DNMTs to DNA, hindering the methylation and decreasing the dissociation, thereby trapping the enzyme and preventing turnover even at other sites.
Published: 2010
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