Author: "Jean-Michel Augereau" - Searchworks@Jio Institute Digital Library Search Results

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31 results on '"Jean-Michel Augereau"'

1. In artemisinin-resistant falciparum malaria parasites, mitochondrial metabolic pathways are essential for survival but not those of apicoplast

Author: Manel Ouji, Thibaud Reyser, Yoshiki Yamaryo-Botté, Michel Nguyen, David Rengel, Axelle Dutreuil, Marlène Marcellin, Odile Burlet-Schiltz, Jean-Michel Augereau, Michael K. Riscoe, Lucie Paloque, Cyrille Botté, and Françoise Benoit-Vical
Subjects: Artemisinin resistance, Metabolism, Apicoplast, Mitochondrion, Quiescence, Infectious and parasitic diseases, RC109-216
Abstract: Emergence and spread of parasite resistance to artemisinins, the first-line antimalarial therapy, threaten the malaria eradication policy. To identify therapeutic targets to eliminate artemisinin-resistant parasites, the functioning of the apicoplast and the mitochondrion was studied, focusing on the fatty acid synthesis type II (FASII) pathway in the apicoplast and the electron transfer chain in the mitochondrion. A significant enrichment of the FASII pathway among the up-regulated genes in artemisinin-resistant parasites under dihydroartemisinin treatment was found, in agreement with published transcriptomic data. However, using GC-MS analyzes of fatty acids, we demonstrated for the first time that the FASII pathway is non-functional, ruling out the use of FASII inhibitors to target artemisinin-resistant parasites. Conversely, by assessing the modulation of the oxygen consumption rate, we evidenced that mitochondrial respiration remains functional and flexible in artemisinin-resistant parasites and even at the quiescent stage. Two novel compounds targeting electron transport chain (ELQ300, ELQ400) efficiently killed quiescent artemisinin-resistant parasites. Therefore, mitochondrial respiration represents a key target for the elimination of artemisinin-resistant persistent Plasmodium falciparum parasites.
Published: 2024
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2. Epigenetic regulation as a therapeutic target in the malaria parasite Plasmodium falciparum

Author: Thibaud Reyser, Lucie Paloque, Jean-Michel Augereau, Luisa Di Stefano, and Françoise Benoit-Vical
Subjects: Plasmodium, Epigenetics, Histone modifications, Epidrugs, Antiplasmodial drugs, Arctic medicine. Tropical medicine, RC955-962, Infectious and parasitic diseases, RC109-216
Abstract: Abstract Over the past thirty years, epigenetic regulation of gene expression has gained increasing interest as it was shown to be implicated in illnesses ranging from cancers to parasitic diseases. In the malaria parasite, epigenetics was shown to be involved in several key steps of the complex life cycle of Plasmodium, among which asexual development and sexual commitment, but also in major biological processes like immune evasion, response to environmental changes or DNA repair. Because epigenetics plays such paramount roles in the Plasmodium parasite, enzymes involved in these regulating pathways represent a reservoir of potential therapeutic targets. This review focuses on epigenetic regulatory processes and their effectors in the malaria parasite, as well as the inhibitors of epigenetic pathways and their potential as new anti-malarial drugs. Such types of drugs could be formidable tools that may contribute to malaria eradication in a context of widespread resistance to conventional anti-malarials.
Published: 2024
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3. Peptide-Alkoxyamine Drugs: An Innovative Approach to Fight Schistosomiasis: 'Digging Their Graves with Their Forks'

Author: Ange W. Embo-Ibouanga, Michel Nguyen, Jean-Patrick Joly, Mathilde Coustets, Jean-Michel Augereau, Lucie Paloque, Nicolas Vanthuyne, Raphaël Bikanga, Anne Robert, Françoise Benoit-Vical, Gérard Audran, Philippe Mellet, Jérôme Boissier, and Sylvain R. A. Marque
Subjects: schistosoma, alkoxyamines, prodrug, new concept, Medicine
Abstract: The expansion of drug resistant parasites sheds a serious concern on several neglected parasitic diseases. Our recent results on cancer led us to envision the use of peptide-alkoxyamines as a highly selective and efficient new drug against schistosome adult worms, the etiological agents of schistosomiasis. Indeed, the peptide tag of the hybrid compounds can be hydrolyzed by worm’s digestive enzymes to afford a highly labile alkoxyamine which homolyzes spontaneously and instantaneously into radicals—which are then used as a drug against Schistosome adult parasites. This approach is nicely summarized as digging their graves with their forks. Several hybrid peptide-alkoxyamines were prepared and clearly showed an activity: two of the tested compounds kill 50% of the parasites in two hours at a concentration of 100 µg/mL. Importantly, the peptide and alkoxyamine fragments that are unable to generate alkyl radicals display no activity. This strong evidence validates the proposed mechanism: a specific activation of the prodrugs by the parasite proteases leading to parasite death through in situ alkyl radical generation.
Published: 2024
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4. Hybrid Peptide-Alkoxyamine Drugs: A Strategy for the Development of a New Family of Antiplasmodial Drugs

Author: Ange W. Embo-Ibouanga, Michel Nguyen, Lucie Paloque, Mathilde Coustets, Jean-Patrick Joly, Jean-Michel Augereau, Nicolas Vanthuyne, Raphaël Bikanga, Naomie Coquin, Anne Robert, Gérard Audran, Jérôme Boissier, Philippe Mellet, Françoise Benoit-Vical, and Sylvain R. A. Marque
Subjects: alkoxyamine, drug resistance, prodrug, malaria, Plasmodium, Organic chemistry, QD241-441
Abstract: The emergence and spread of drug-resistant Plasmodium falciparum parasites shed a serious concern on the worldwide control of malaria, the most important tropical disease in terms of mortality and morbidity. This situation has led us to consider the use of peptide-alkoxyamine derivatives as new antiplasmodial prodrugs that could potentially be efficient in the fight against resistant malaria parasites. Indeed, the peptide tag of the prodrug has been designed to be hydrolysed by parasite digestive proteases to afford highly labile alkoxyamines drugs, which spontaneously and instantaneously homolyse into two free radicals, one of which is expected to be active against P. falciparum. Since the parasite enzymes should trigger the production of the active drug in the parasite’s food vacuoles, our approach is summarized as “to dig its grave with its fork”. However, despite promising sub-micromolar IC50 values in the classical chemosensitivity assay, more in-depth tests evidenced that the anti-parasite activity of these compounds could be due to their cytostatic activity rather than a truly anti-parasitic profile, demonstrating that the antiplasmodial activity cannot be based only on measuring antiproliferative activity. It is therefore imperative to distinguish, with appropriate tests, a genuinely parasiticidal activity from a cytostatic activity.
Published: 2024
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5. 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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6. Reactive Oxygen Species as the Brainbox in Malaria Treatment

Author: Chinedu Ogbonnia Egwu, Jean-Michel Augereau, Karine Reybier, and Françoise Benoit-Vical
Subjects: ROS, antimalarials, Plasmodium falciparum, malaria and oxidative stress, Therapeutics. Pharmacology, RM1-950
Abstract: Several measures are in place to combat the worldwide spread of malaria, especially in regions of high endemicity. In part, most common antimalarials, such as quinolines and artemisinin and its derivatives, deploy an ROS-mediated approach to kill malaria parasites. Although some antimalarials may share similar targets and mechanisms of action, varying levels of reactive oxygen species (ROS) generation may account for their varying pharmacological activities. Regardless of the numerous approaches employed currently and in development to treat malaria, concerningly, there has been increasing development of resistance by Plasmodium falciparum, which can be connected to the ability of the parasites to manage the oxidative stress from ROS produced under steady or treatment states. ROS generation has remained the mainstay in enforcing the antiparasitic activity of most conventional antimalarials. However, a combination of conventional drugs with ROS-generating ability and newer drugs that exploit vital metabolic pathways, such antioxidant machinery, could be the way forward in effective malaria control.
Published: 2021
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7. Alkoxyamines Designed as Potential Drugs against Plasmodium and Schistosoma Parasites

Author: Thibaud Reyser, Tung H. To, Chinedu Egwu, Lucie Paloque, Michel Nguyen, Alexandre Hamouy, Jean-Luc Stigliani, Christian Bijani, Jean-Michel Augereau, Jean-Patrick Joly, Julien Portela, Jeffrey Havot, Sylvain R. A. Marque, Jérôme Boissier, Anne Robert, Françoise Benoit-Vical, and Gérard Audran
Subjects: alkoxyamine, alkylation, heme, malaria, radical chemistry, schistosomiasis, Organic chemistry, QD241-441
Abstract: Malaria and schistosomiasis are major infectious causes of morbidity and mortality in the tropical and sub-tropical areas. Due to the widespread drug resistance of the parasites, the availability of new efficient and affordable drugs for these endemic pathologies is now a critical public health issue. In this study, we report the design, the synthesis and the preliminary biological evaluation of a series of alkoxyamine derivatives as potential drugs against Plasmodium and Schistosoma parasites. The compounds (RS/SR)-2F, (RR/SS)-2F, and 8F, having IC50 values in nanomolar range against drug-resistant P. falciparum strains, but also five other alkoxyamines, inducing the death of all adult worms of S. mansoni in only 1 h, can be considered as interesting chemical starting points of the series for improvement of the activity, and further structure activity, relationship studies. Moreover, investigation of the mode of action and the rate constants kd for C-ON bond homolysis of new alkoxyamines is reported, showing a possible alkyl radical mediated biological activity. A theoretical chemistry study allowed us to design new structures of alkoxyamines in order to improve the selectivity index of these drugs.
Published: 2020
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8. Hybrid Gold(I) NHC-Artemether Complexes to Target Falciparum Malaria Parasites

Author: Manel Ouji, Guillaume Barnoin, Álvaro Fernández Álvarez, Jean-Michel Augereau, Catherine Hemmert, Françoise Benoit-Vical, and Heinz Gornitzka
Subjects: malaria, Plasmodium falciparum, gold, NHC-ligands, hybrid molecules, drug resistance, Organic chemistry, QD241-441
Abstract: The emergence of Plasmodium falciparum parasites, responsible for malaria disease, resistant to antiplasmodial drugs including the artemisinins, represents a major threat to public health. Therefore, the development of new antimalarial drugs or combinations is urgently required. In this context, several hybrid molecules combining a dihydroartemisinin derivative and gold(I) N-heterocyclic carbene (NHC) complexes have been synthesized based on the different modes of action of the two compounds. The antiplasmodial activity of these molecules was assessed in vitro as well as their cytotoxicity against mammalian cells. All the hybrid molecules tested showed efficacy against P. falciparum, in a nanomolar range for the most active, associated with a low cytotoxicity. However, cross-resistance between artemisinin and these hybrid molecules was evidenced. These results underline a fear about the risk of cross-resistance between artemisinins and new antimalarial drugs based on an endoperoxide part. This study thus raises concerns about the use of such molecules in future therapeutic malaria policies.
Published: 2020
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9. An LC–MS Assay to Measure Superoxide Radicals and Hydrogen Peroxide in the Blood System

Author: Ioannis Tsamesidis, Chinedu O. Egwu, Pierre Pério, Jean-Michel Augereau, Françoise Benoit-Vical, and Karine Reybier
Subjects: liquid-chromatography, mass spectrometry, superoxide radicals, hydrogen peroxide species, red blood cells, human plasma, Microbiology, QR1-502
Abstract: Red blood cells are constantly exposed to reactive species under physiological or pathological conditions or during administration of xenobiotics. Regardless of the source, its accurate quantification is paramount in the area of theragnostics, which had been elusive up until now. Even if there are a lot of approaches to evaluate the oxidative stress, very sensitive methods are missing for the blood system. We therefore sought to apply a highly sensitive approach, by liquid chromatography coupled to mass spectrometry (UPLC–MS), for the quantification of reactive species such as superoxide radical and hydrogen peroxide using dihydroethidium (DHE) and coumarin boronic acid (CBA) probes respectively through the detection of 2-hydroxyethidium (2OH-E+) and 7-hydroxycoumarin (COH). The use of the high-resolution mass spectrometry associated to UPLC ensured a selective detection of superoxide and hydrogen peroxide in the blood system under diverse conditions such as oxidized red blood cells (RBCs), untreated and treated parasitized RBCs. Moreover, this technique allowed the determination of reactive species in human plasma. This protocol provides a huge opportunity for in-depth study of several pathological conditions vis-a-vis their treatment in modern medicine.
Published: 2020
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10. Young Sprague Dawley rats infected by Plasmodium berghei: A relevant experimental model to study cerebral malaria.

Author: Sokhna Keita Alassane, Marie-Laure Nicolau-Travers, Sandie Menard, Olivier Andreoletti, Jean-Pierre Cambus, Noémie Gaudre, Myriam Wlodarczyk, Nicolas Blanchard, Antoine Berry, Sarah Abbes, David Colongo, Babacar Faye, Jean-Michel Augereau, Caroline Lacroux, Xavier Iriart, and Françoise Benoit-Vical
Subjects: Medicine, Science
Abstract: Cerebral malaria (CM) is the most severe manifestation of human malaria yet is still poorly understood. Mouse models have been developed to address the subject. However, their relevance to mimic human pathogenesis is largely debated. Here we study an alternative cerebral malaria model with an experimental Plasmodium berghei Keyberg 173 (K173) infection in Sprague Dawley rats. As in Human, not all infected subjects showed cerebral malaria, with 45% of the rats exhibiting Experimental Cerebral Malaria (ECM) symptoms while the majority (55%) of the remaining rats developed severe anemia and hyperparasitemia (NoECM). These results allow, within the same population, a comparison of the noxious effects of the infection between ECM and severe malaria without ECM. Among the ECM rats, 77.8% died between day 5 and day 12 post-infection, while the remaining rats were spontaneously cured of neurological signs within 24-48 hours. The clinical ECM signs observed were paresis quickly evolving to limb paralysis, global paralysis associated with respiratory distress, and coma. The red blood cell (RBC) count remained normal but a drastic decrease of platelet count and an increase of white blood cell numbers were noted. ECM rats also showed a decrease of glucose and total CO2 levels and an increase of creatinine levels compared to control rats or rats with no ECM. Assessment of the blood-brain barrier revealed loss of integrity, and interestingly histopathological analysis highlighted cyto-adherence and sequestration of infected RBCs in brain vessels from ECM rats only. Overall, this ECM rat model showed numerous clinical and histopathological features similar to Human CM and appears to be a promising model to achieve further understanding the CM pathophysiology in Humans and to evaluate the activity of specific antimalarial drugs in avoiding/limiting cerebral damages from malaria.
Published: 2017
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11. Mutation in the Plasmodium falciparum BTB/POZ Domain of K13 Protein Confers Artemisinin Resistance

Author: Nina F. Gnädig, Françoise Benoit-Vical, Romain Coppée, Jérôme Clain, David A. Fidock, Karamoko Niaré, Jean-Michel Augereau, Barbara H. Stokes, Lucie Paloque, Laboratoire de chimie de coordination (LCC), Institut de Chimie de Toulouse (ICT), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), New Antimalarial Molecules and Pharmacological Approaches (ERL1289), Centre d'investigation clinique de Toulouse (CIC 1436), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Pôle Santé publique et médecine publique [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Université Toulouse III - Paul Sabatier (UT3), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Institut de pharmacologie et de biologie structurale (IPBS), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Mère et enfant en milieu tropical : pathogènes, système de santé et transition épidémiologique (MERIT - UMR_D 261), Institut de Recherche pour le Développement (IRD)-Université Paris Cité (UPCité), Columbia University Irving Medical Center (CUIMC), Malaria Research and Training Center [Bamako, Mali], Université de Bamako, AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre National de la Recherche Scientifique (CNRS), NIH (R01 AI109023), WorldWide Antimalarial Resistance Network (WWARN), ANR-17-CE15-0013,PlasmoPrim,Elucider les mécanismes d'action de deux agents redox antipaludiques aux propriétés gametocytocides et bloquant la transmission -- de la levure aux parasites du paludisme(2017), Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Pôle Santé publique et médecine publique [CHU Toulouse], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Mère et enfant en milieu tropical : pathogènes, système de santé et transition épidémiologique (MERIT - UMR_D 216), Gulli, Marie-Hélène, and Elucider les mécanismes d'action de deux agents redox antipaludiques aux propriétés gametocytocides et bloquant la transmission -- de la levure aux parasites du paludisme - - PlasmoPrim2017 - ANR-17-CE15-0013 - AAPG2017 - VALID
Subjects: medicine.medical_treatment, Plasmodium falciparum, Drug Resistance, Protozoan Proteins, Dihydroartemisinin, medicine.disease_cause, Epidemiology and Surveillance, Antimalarials, parasitic diseases, medicine, Coding region, CRISPR, [CHIM.COOR]Chemical Sciences/Coordination chemistry, Pharmacology (medical), Artemisinin, BTB/POZ domain, Gene, Pharmacology, Mutation, biology, K13 mutation, [CHIM.COOR] Chemical Sciences/Coordination chemistry, Editor's Pick, biology.organism_classification, Virology, Artemisinins, Malaria, Infectious Diseases, Artemisinin resistance, BTB-POZ Domain, medicine.drug
Abstract: International audience; Partial artemisinin resistance, defined in patients as a delayed parasite clearance following artemisinin-based treatment, is conferred by non-synonymous mutations in the Kelch beta-propeller domain of the Plasmodium falciparum k13 (pfk13) gene. Here, we carried out in vitro selection over a 1-year period on a West African P. falciparum strain isolated from Kolle (Mali) under a dose-escalating artemisinin regimen. After 18 cycles of sequential drug pressure, the selected parasites exhibited enhanced survival to dihydroartemisinin in the ring-stage survival assay (RSA0-3h = 9.2%). Sanger and whole-genome sequence analyses identified the PfK13 P413A mutation, localized in the BTB/POZ domain, upstream of the propeller domain. This mutation was sufficient to confer in vitro artemisinin resistance when introduced into the PfK13 coding sequence of the parasite strain Dd2 by CRISPR/Cas9 gene editing. These results together with structural studies of the protein demonstrate that the propeller domain is not the sole in vitro mediator of PfK13-mediated artemisinin resistance, and highlight the importance of monitoring for mutations throughout PfK13.
Published: 2022
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12. Reactive Oxygen Species as the Brainbox in Malaria Treatment

Author: Françoise Benoit-Vical, Jean-Michel Augereau, Karine Reybier, Chinedu O. Egwu, Pharmacochimie et Biologie pour le Développement (PHARMA-DEV), Institut de Recherche pour le Développement (IRD)-Institut de Chimie de Toulouse (ICT), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT), Alex Ekwueme Federal University Ndufu-Alike, Ikwo (AE-FUNAI), Institut de pharmacologie et de biologie structurale (IPBS), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), New Antimalarial Molecules and Pharmacological Approaches (ERL1289), Centre d'investigation clinique de Toulouse (CIC 1436), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Pôle Santé publique et médecine publique [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Université Toulouse III - Paul Sabatier (UT3), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Laboratoire de chimie de coordination (LCC), Institut de Chimie de Toulouse (ICT), Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), CNRS (Centre National de la Recherche Scientifique, France), Université Paul Sabatier, Toulouse III (France), IRD (Institut de Recherche pour le Développement, France), Institut de Recherche pour le Développement (IRD)-Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Pôle Santé publique et médecine publique [CHU Toulouse], Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), and Pagès, Nathalie
Subjects: malaria and oxidative stress, Physiology, [SDV]Life Sciences [q-bio], Clinical Biochemistry, Plasmodium falciparum, RM1-950, Review, medicine.disease_cause, Biochemistry, antimalarials, parasitic diseases, medicine, Artemisinin, Molecular Biology, chemistry.chemical_classification, Reactive oxygen species, biology, ROS, Cell Biology, biology.organism_classification, medicine.disease, [SDV] Life Sciences [q-bio], chemistry, Immunology, Therapeutics. Pharmacology, Malaria control, Malaria, Oxidative stress, medicine.drug
Abstract: International audience; Several measures are in place to combat the worldwide spread of malaria, especially in regions of high endemicity. In part, most common antimalarials, such as quinolines and artemisinin and its derivatives, deploy an ROS-mediated approach to kill malaria parasites. Although some antimalarials may share similar targets and mechanisms of action, varying levels of reactive oxygen species (ROS) generation may account for their varying pharmacological activities. Regardless of the numerous approaches employed currently and in development to treat malaria, concerningly, there has been increasing development of resistance by Plasmodium falciparum, which can be connected to the ability of the parasites to manage the oxidative stress from ROS produced under steady or treatment states. ROS generation has remained the mainstay in enforcing the antiparasitic activity of most conventional antimalarials. However, a combination of conventional drugs with ROS-generating ability and newer drugs that exploit vital metabolic pathways, such antioxidant machinery, could be the way forward in effective malaria control.
Published: 2021
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13. Resistance to artemisinin in falciparum malaria parasites: A redox-mediated phenomenon

Author: Chinedu O, Egwu, Pierre, Pério, Jean-Michel, Augereau, Ioannis, Tsamesidis, Françoise, Benoit-Vical, and Karine, Reybier
Subjects: Antimalarials, Plasmodium falciparum, Drug Resistance, Animals, Parasites, Malaria, Falciparum, Oxidation-Reduction, Artemisinins, Malaria
Abstract: Malaria remains a major public health disease due to its high yearly mortality and morbidity. Resistance to the gold standard drug, artemisinin, is worrisome and needs better understanding in order to be overcome. In this work, we sought to study whether redox processes are involved in artemisinin resistance. As artemisinin is known to act among others via production of reactive species, we first compared the production of reactive oxygen species and concomitant protein oxidation in artemisinin-sensitive and artemisinin-resistant parasites when treated with artemisinin. The results undoubtedly demonstrated, using different original methods, that the level of ROS, including superoxide production, and oxidized protein were lower in the resistant strain. Interestingly, the major in-between strain difference was reported at the earlier ring stages, which are the forms able to enter in a quiescence state according to the ART resistance phenomenon. Moreover, we demonstrated a better homeostasis regulation in relation with higher expression of antioxidants in the artemisinin-resistant parasites than their sensitive counterparts after artemisinin exposure, notably, superoxide dismutase and the glutathione (GSH) system. These findings enrich the body of knowledges about the multifaceted mechanism of artemisinin resistance and will help in the design and development of newer antimalarials strategies active against resistant parasites.
Published: 2021

14. The antimalarial MMV688533 provides potential for single-dose cures with a high barrier to Plasmodium falciparum parasite resistance

Author: Mohammed H Cherkaoui-Rbati, Roland A. Cooper, Nina F. Gnädig, Iñigo Angulo-Barturen, Tomas Yeo, Sridevi Bashyam, Rintis Noviyanti, James M. Murithi, Gilles Courtemanche, Philip J. Rosenthal, María Belén Jiménez-Díaz, Laurent Sallé, Cécile Pascal, Rita Merino, Gilles Tuffal, Jutta Marfurt, Sergio Wittlin, Shivendra Singh, Marie José Cabanis, Lidiya Bebrevska, Jean Michel Augereau, Laura M. Sanz, Jean Michel Guillon, Sachel Mok, Paul Desert, Kelly Rubiano, Alain Pellet, Jacquin C. Niles, Guillaume Louit, Anne-Catrin Uhlemann, Nadir Bessila, Thierry Vermat, Simon Campbell, Didier Leroy, Tanguy Bozec, Jérôme Menegotto, Michel Doubovetzky, Xavier Boulenc, Benjamin Blasco, Nathalie Gobeau, Francisco-Javier Gamo, Sylvie Klieber, Elie Giraud, Jayan Joseph, Charisse Flerida A. Pasaje, Delphine Baud, Laurent Fraisse, Fanny Escudié, Jade Bath, Marie Françoise Nicolas, Mélanie Rouillier, David A. Fidock, Grennady Wirjanata, Ric N. Price, and Patrick K Tumwebaze
Subjects: 0301 basic medicine, Point mutation, 030106 microbiology, Plasmodium falciparum, General Medicine, Biology, Pharmacology, Endocytosis, medicine.disease, biology.organism_classification, In vitro, 03 medical and health sciences, 030104 developmental biology, medicine, NSG mouse, Mode of action, Intracellular, Malaria
Abstract: The emergence and spread of Plasmodium falciparum resistance to first-line antimalarials creates an imperative to identify and develop potent preclinical candidates with distinct modes of action. Here, we report the identification of MMV688533, an acylguanidine that was developed following a whole-cell screen with compounds known to hit high-value targets in human cells. MMV688533 displays fast parasite clearance in vitro and is not cross-resistant with known antimalarials. In a P. falciparum NSG mouse model, MMV688533 displays a long-lasting pharmacokinetic profile and excellent safety. Selection studies reveal a low propensity for resistance, with modest loss of potency mediated by point mutations in PfACG1 and PfEHD. These proteins are implicated in intracellular trafficking, lipid utilization, and endocytosis, suggesting interference with these pathways as a potential mode of action. This preclinical candidate may offer the potential for a single low-dose cure for malaria.
Published: 2021

15. Superoxide: A major role in the mechanism of action of essential antimalarial drugs

Author: Karine Reybier, Pierre Perio, Chinedu O. Egwu, Ioannis Tsamesidis, Jean-Michel Augereau, Françoise Benoit-Vical, Pharmacochimie et Biologie pour le Développement (PHARMA-DEV), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie de Toulouse (ICT-FR 2599), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Institut de Chimie du CNRS (INC)-Institut de Recherche pour le Développement (IRD), Alex Ekwueme Federal University Ndufu-Alike, Ikwo (AE-FUNAI), Laboratoire de chimie de coordination (LCC), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Institut de Chimie du CNRS (INC)-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, New Antimalarial Molecules and Pharmacological Approaches (ERL1289), Centre d'investigation clinique de Toulouse (CIC 1436), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Recherche pour le Développement (IRD)-Institut de Chimie de Toulouse (ICT), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT), Institut de Chimie de Toulouse (ICT), Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Université de Toulouse (UT)-Université de Toulouse (UT)-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)-Pôle Santé publique et médecine publique [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Université Toulouse III - Paul Sabatier (UT3), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), and ANR-16-CE35-0003,INMAR,Réseau intégré des mécanismes de quiescence & clairance impliqués dans la résistance à l'artémisinine chez Plasmodium(2016)
Subjects: 0301 basic medicine, Artemisinins, medicine.medical_treatment, Plasmodium falciparum, Drug Resistance, Dihydroartemisinin, Pharmacology, Mechanism of action, Biochemistry, 03 medical and health sciences, chemistry.chemical_compound, Antimalarials, 0302 clinical medicine, Superoxides, Chloroquine, Physiology (medical), parasitic diseases, medicine, [CHIM.COOR]Chemical Sciences/Coordination chemistry, Artemisinin, biology, Superoxide radicals, Superoxide, biology.organism_classification, 3. Good health, LC-MS, 030104 developmental biology, chemistry, medicine.symptom, Drugs, Essential, 030217 neurology & neurosurgery, Atovaquone, medicine.drug
Abstract: International audience; Understanding the mode of action of antimalarials is central to optimizing their use and the discovery of new therapeutics. Currently used antimalarials belong to a limited series of chemical structures and their mechanisms of action are coutinuously debated. Whereas the involvement of reactive species that in turn kill the parasites sensitive to oxidative stress, is accepted for artemisinins, little is known about the generation of such species in the case of quinolines or hydroxynaphtoquinone. Moreover, the nature of the reactive species involved has never been characterized in Plasmodium-infected erythrocytes. The aim of this work was to determine and elucidate the production of the primary radical, superoxide in Plasmodium-infected erythrocytes treated with artemisinin, dihydroartemisinin, chloroquine and atovaquone, as representatives of three major classes of antimalarials. The intracellular generation of superoxide was quantified by liquid chromatography coupled to mass spectrometry (LC-MS). We demonstrated that artemisinins, atovaquone and to a lesser extent chloroquine, generate significant levels of superoxide radicals in Plasmodium falciparum sensitive strains. More so, the production of superoxide was lowered in chloroquine-resistant strain of Plasmodium treated with chloroquine. These results consolidate the knowledge about the mechanism of action of these different antimalarials and should be taken into consideration in the design of future drugs to fight drug-resistant parasites.
Published: 2021
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16. The antimalarial MMV688533 provides potential for single-dose cures with a high barrier to

Author: James M, Murithi, Cécile, Pascal, Jade, Bath, Xavier, Boulenc, Nina F, Gnädig, Charisse Flerida A, Pasaje, Kelly, Rubiano, Tomas, Yeo, Sachel, Mok, Sylvie, Klieber, Paul, Desert, María Belén, Jiménez-Díaz, Jutta, Marfurt, Mélanie, Rouillier, Mohammed H, Cherkaoui-Rbati, Nathalie, Gobeau, Sergio, Wittlin, Anne-Catrin, Uhlemann, Ric N, Price, Grennady, Wirjanata, Rintis, Noviyanti, Patrick, Tumwebaze, Roland A, Cooper, Philip J, Rosenthal, Laura M, Sanz, Francisco Javier, Gamo, Jayan, Joseph, Shivendra, Singh, Sridevi, Bashyam, Jean Michel, Augereau, Elie, Giraud, Tanguy, Bozec, Thierry, Vermat, Gilles, Tuffal, Jean-Michel, Guillon, Jérôme, Menegotto, Laurent, Sallé, Guillaume, Louit, Marie-José, Cabanis, Marie Françoise, Nicolas, Michel, Doubovetzky, Rita, Merino, Nadir, Bessila, Iñigo, Angulo-Barturen, Delphine, Baud, Lidiya, Bebrevska, Fanny, Escudié, Jacquin C, Niles, Benjamin, Blasco, Simon, Campbell, Gilles, Courtemanche, Laurent, Fraisse, Alain, Pellet, David A, Fidock, and Didier, Leroy
Subjects: Antimalarials, Plasmodium falciparum, Animals, Parasites, Malaria, Falciparum, Endocytosis, Article, Malaria
Abstract: The emergence and spread of Plasmodium falciparum resistance to first-line antimalarials creates an imperative to identify and develop potent preclinical candidates with distinct modes of action. Here, we report the identification of MMV688533, an acylguanidine that was developed following a whole-cell screen with compounds known to hit high-value targets in human cells. MMV688533 displays fast parasite clearance in vitro and is not cross-resistant with known antimalarials. In a P. falciparum NSG mouse model, MMV688533 displays a long-lasting pharmacokinetic profile and excellent safety. Selection studies reveal a low propensity for resistance, with modest loss of potency mediated by point mutations in PfACG1 and PfEHD. These proteins are implicated in intracellular trafficking, lipid utilization, and endocytosis, suggesting interference with these pathways as a potential mode of action. This preclinical candidate may offer the potential for a single low-dose cure for malaria.
Published: 2021

17. Novel molecule combinations and corresponding hybrids targeting artemisinin-resistant Plasmodium falciparum parasites

Author: Manel Ouji, Tony Jimenez, Michel Nguyen, Céline Deraeve, Romain Mustière, Jean-Michel Augereau, Françoise Benoit-Vical, Laboratoire de chimie de coordination (LCC), Institut de Chimie de Toulouse (ICT), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Institut de pharmacologie et de biologie structurale (IPBS), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), New Antimalarial Molecules and Pharmacological Approaches (ERL1289), Centre d'investigation clinique de Toulouse (CIC 1436), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Pôle Santé publique et médecine publique [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Université Toulouse III - Paul Sabatier (UT3), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Centre National de la Recherche Scientifique, Sanofi-Institut Pasteur award, ANR-16-CE35-0003,INMAR,Réseau intégré des mécanismes de quiescence & clairance impliqués dans la résistance à l'artémisinine chez Plasmodium(2016), Gulli, Marie-Hélène, Réseau intégré des mécanismes de quiescence & clairance impliqués dans la résistance à l'artémisinine chez Plasmodium - - INMAR2016 - ANR-16-CE35-0003 - AAPG2016 - VALID, Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Pôle Santé publique et médecine publique [CHU Toulouse], Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Clinical Biochemistry, Drug Resistance, Pharmaceutical Science, Quiescence, 01 natural sciences, Biochemistry, Antimalarial drug, Parasitic Sensitivity Tests, Drug Discovery, Artemisinin, Malaria, Falciparum, Drug combination, media_common, biology, Molecular Structure, Chemistry, Mefloquine, Artemisinins, 3. Good health, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Artemisinin resistance, Molecular Medicine, Pharmacophore, Atovaquone, medicine.drug, Drug, media_common.quotation_subject, Plasmodium falciparum, Context (language use), Antimalarials, Structure-Activity Relationship, parasitic diseases, medicine, Humans, Molecular Biology, [SDV.MP] Life Sciences [q-bio]/Microbiology and Parasitology, Dose-Response Relationship, Drug, 010405 organic chemistry, Organic Chemistry, Hybrid molecule, medicine.disease, biology.organism_classification, Triclosan, 0104 chemical sciences, 010404 medicinal & biomolecular chemistry, Malaria
Abstract: International audience; Malaria is still considered as the major parasitic disease and the development of artemisinin resistance does not improve this alarming situation. Based on the recent identification of relevant malaria targets in the artemisinin resistance context, novel drug combinations were evaluated against artemisinin-sensitive and artemisinin-resistant Plasmodium falciparum parasites. Corresponding hybrid molecules were also synthesized and evaluated for comparison with combinations and individual pharmacophores (e.g. atovaquone, mefloquine or triclosan). Combinations and hybrids showed remarkable antimalarial activity (IC50 = 0.6 to 1.1 nM for the best compounds), strong selectivity, and didn’t present any cross-resistance with artemisinin. Moreover, the combination triclosan + atovaquone showed high activity against artemisinin-resistant parasites at the quiescent stage but the corresponding hybrid lost this pharmacological property. This result is essential since only few molecules active against quiescent artemisinin-resistant parasites are reported. Our promising results highlight the potential of these combinations and paves the way for pharmacomodulation work on the best hybrids.
Published: 2020
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18. Identification of compounds active against quiescent artemisinin-resistant Plasmodium falciparum parasites via the quiescent-stage survival assay (QSA)

Author: Sandie Menard, Manel Ouji, Michel Nguyen, Lucie Paloque, Thibaud Reyser, Françoise Benoit-Vical, Jean-Michel Augereau, Benoit Witkowski, Laboratoire de chimie de coordination (LCC), Institut de Chimie de Toulouse (ICT), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Institut de pharmacologie et de biologie structurale (IPBS), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Pharmacochimie et Biologie pour le Développement (PHARMA-DEV), Institut de Recherche pour le Développement (IRD)-Institut de Chimie de Toulouse (ICT), Université de Toulouse (UT), Malaria Molecular Epidemiology (MMEU), Institut Pasteur du Cambodge, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Institut National de la Santé et de la Recherche Médicale (INSERM), CNRS, ANR-13-BSV3-0018,MALARTRES,Résistance de Plasmodium aux antipaludiques de la famille des artémisinines(2013), ANR-14-CE35-0003,CAP-G4,Development of photo-reactive probes to capture G-quadruplex DNA in complex with endogenous proteins and exogenous synthetic ligands(2014), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Institut de Chimie du CNRS (INC)-Institut de Recherche pour le Développement (IRD), Malaria Molecular Epidemiology, Gulli, Marie-Hélène, Blanc 2013 - Résistance de Plasmodium aux antipaludiques de la famille des artémisinines - - MALARTRES2013 - ANR-13-BSV3-0018 - Blanc 2013 - VALID, Appel à projets générique - Development of photo-reactive probes to capture G-quadruplex DNA in complex with endogenous proteins and exogenous synthetic ligands - - CAP-G42014 - ANR-14-CE35-0003 - Appel à projets générique - VALID, Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Institut de Recherche pour le Développement (IRD)-Institut de Chimie de Toulouse (ICT-FR 2599), and Université Fédérale Toulouse Midi-Pyrénées
Subjects: Microbiology (medical), [CHIM.THER] Chemical Sciences/Medicinal Chemistry, Plasmodium falciparum, Drug Resistance, Protozoan Proteins, Context (language use), Drug resistance, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, Pharmacology, 03 medical and health sciences, Antimalarials, Chloroquine, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, parasitic diseases, medicine, Animals, Pharmacology (medical), Parasites, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, Artemisinin, Malaria, Falciparum, 030304 developmental biology, 0303 health sciences, biology, 030306 microbiology, Drug discovery, biology.organism_classification, Artemisinins, 3. Good health, Infectious Diseases, Drug development, [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Cambodia, Artemisinine, Atovaquone, [SDV.MP.PAR] Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, medicine.drug
Abstract: Background Quiescence is an unconventional mechanism of Plasmodium survival, mediating artemisinin resistance. This phenomenon increases the risk of clinical failures following artemisinin-based combination therapies (ACTs) by slowing parasite clearance and allowing the selection of parasites resistant to partner drugs. Objectives To thwart this multiresistance, the quiescent state of artemisinin-resistant parasites must be taken into consideration from the very early stages of the drug discovery process. Methods We designed a novel phenotypic assay we have named the quiescent-stage survival assay (QSA) to assess the antiplasmodial activity of drugs on quiescent parasites. This assay was first validated on quiescent forms from different artemisinin-resistant parasite lines (laboratory strain and field isolates), using two reference drugs with different mechanisms of action: chloroquine and atovaquone. Furthermore, the efficacies of different partner drugs of artemisinins used in ACTs were investigated against both laboratory strains and field isolates from Cambodia. Results Our results highlight that because of the mechanism of quiescence and the respective pharmacological targets of drugs, drug efficacies on artemisinin-resistant parasites may be different between quiescent parasites and their proliferating forms. Conclusions These data confirm the high relevance of adding the chemosensitivity evaluation of quiescent parasites by the specific in vitro QSA to the antiplasmodial drug development process in the current worrisome context of artemisinin resistance.
Published: 2020
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19. Antiprotozoal properties of Indonesian medicinal plant extracts

Author: Lucie Paloque, Alexis Valentin, Arba Pramundita Ramadani, Hady Anshory Tamhid, Hugo Belda, Mustofa, Françoise Benoit-Vical, Jumina, Mahardika Agus Wijayanti, Jean-Michel Augereau, Masriani, Laboratoire de chimie de coordination (LCC), Institut de Chimie de Toulouse (ICT), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Department of Pharmacology and Therapy, Faculty of Medicine, Universitas Gadjah Mada, Universitas Gadjah Mada, Department of Pharmacy, Faculty of Science & Mathematics, Islamic University of Indonesia, Islamic University of Indonesia, Pharmacochimie et Biologie pour le Développement (PHARMA-DEV), Institut de Recherche pour le Développement (IRD)-Institut de Chimie de Toulouse (ICT), Université de Toulouse (UT), Department of Chemistry, Faculty of Mathematics and Natural Science, Gadjah Mada University, Department of Parasitology, Faculty of Medicine, Universitas Gadjah Mada, Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Institut de Chimie du CNRS (INC)-Institut de Recherche pour le Développement (IRD), and Université Fédérale Toulouse Midi-Pyrénées
Subjects: 0301 basic medicine, Antiparasitic drugs, medicine.drug_class, Plasmodium falciparum, 030106 microbiology, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, 01 natural sciences, 03 medical and health sciences, parasitic diseases, Botany, medicine, Pycnarrhena cauliflora, Babesia divergens, biology, Traditional medicine, Antiparasitic Drugs, Tithonia, biology.organism_classification, 3. Good health, 0104 chemical sciences, 010404 medicinal & biomolecular chemistry, Complementary and alternative medicine, Indonesia, Antiprotozoal, Leishmania infantum, Tinospora crispa
Abstract: International audience; Tithonia diversifolia, Cyclea barbata, Tinospora crispa, Arcangelisia flava, Pycnarrhena cauliflora are plants used in Indonesia for the traditional treatment of malaria. In the search for new antiparasitic drugs, the parts traditionally used of these 5 plants were extracted with ethanol and then fractionated with various solvents and evaluated in vitro against Plasmodium falciparum and also against Babesia divergens and Leishmania infantum. Seven crude plant extracts out of 25 tested displayed high antimalarial activities with IC50
Published: 2018
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20. Alkoxyamines Designed as Potential Drugs against Plasmodium and Schistosoma Parasites

Author: Chinedu O. Egwu, Thibaud Reyser, Jean-Luc Stigliani, Gérard Audran, Tung H To, Christian Bijani, Sylvain R. A. Marque, Françoise Benoit-Vical, Alexandre Hamouy, Jeffrey Havot, Michel Nguyen, Jérôme Boissier, Anne Robert, Lucie Paloque, Jean-Michel Augereau, Jean-Patrick Joly, Julien Portela, Laboratoire de chimie de coordination (LCC), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Institut de Chimie du CNRS (INC)-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, Institut de Chimie Radicalaire (ICR), Aix Marseille Université (AMU)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), S.A.S ParaDev, Interactions Hôtes-Pathogènes-Environnements (IHPE), 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), Institut National de la Santé et de la Recherche Médicale (INSERM), Gulli, Marie-Hélène, Stratégie thérapeutique par voie radicalaire pour combattre des maladies parasitaires - - RADICAL2017 - ANR-17-CE18-0017 - AAPG2017 - VALID, Institut de Chimie de Toulouse (ICT-FR 2599), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), 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), Aix-Marseille Université, Université de Perpignan, Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (Inserm), ANR-17-CE18-0017,RADICAL,Stratégie thérapeutique par voie radicalaire pour combattre des maladies parasitaires(2017), Institut de Chimie de Toulouse (ICT), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), and Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Alkylation, [CHIM.THER] Chemical Sciences/Medicinal Chemistry, Plasmodium falciparum, malaria, Pharmaceutical Science, Schistosomiasis, Drug resistance, Heme, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, Pharmacology, 010402 general chemistry, 01 natural sciences, Plasmodium, Article, Analytical Chemistry, lcsh:QD241-441, Antimalarials, lcsh:Organic chemistry, schistosomiasis, Drug Discovery, parasitic diseases, Ic50 values, medicine, Animals, Humans, radical chemistry, Physical and Theoretical Chemistry, heme, alkylation, Schistosoma, Biological evaluation, Anthelmintics, biology, 010405 organic chemistry, Organic Chemistry, Radical chemistry, Biological activity, Schistosoma mansoni, Alkoxyamine, biology.organism_classification, medicine.disease, 3. Good health, 0104 chemical sciences, Malaria, Chemistry (miscellaneous), Molecular Medicine, alkoxyamine
Abstract: Malaria and schistosomiasis are major infectious causes of morbidity and mortality in the tropical and sub-tropical areas. Due to the widespread drug resistance of the parasites, the availability of new efficient and affordable drugs for these endemic pathologies is now a critical public health issue. In this study, we report the design, the synthesis and the preliminary biological evaluation of a series of alkoxyamine derivatives as potential drugs against Plasmodium and Schistosoma parasites. The compounds (RS/SR)-2F, (RR/SS)-2F, and 8F, having IC50 values in nanomolar range against drug-resistant P. falciparum strains, but also five other alkoxyamines, inducing the death of all adult worms of S. mansoni in only 1 h, can be considered as interesting chemical starting points of the series for improvement of the activity, and further structure activity, relationship studies. Moreover, investigation of the mode of action and the rate constants kd for C-ON bond homolysis of new alkoxyamines is reported, showing a possible alkyl radical mediated biological activity. A theoretical chemistry study allowed us to design new structures of alkoxyamines in order to improve the selectivity index of these drugs.
Published: 2020
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21. [Plasmodium resistance, a brake on its eradication]

Author: Lucie, Paloque, Jean-Michel, Augereau, and Françoise, Benoit-Vical
Subjects: Antimalarials, Plasmodium, Drug Resistance, Humans, Malaria, Falciparum
Published: 2019

22. Résistance de l’agent du paludisme, Plasmodium falciparum aux combinaisons thérapeutiques à base d’artémisinine (ACTs) : Craintes d’une chimiorésistance généralisée

Author: Jean-Michel Augereau, Françoise Benoit-Vical, and Lucie Paloque
Subjects: 0301 basic medicine, Drug, Artemisinins, biology, business.industry, media_common.quotation_subject, Plasmodium falciparum, General Medicine, Drug resistance, biology.organism_classification, medicine.disease, Virology, Plasmodium, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Pharmacotherapy, parasitic diseases, medicine, 030212 general & internal medicine, Artemisinin, business, Malaria, media_common, medicine.drug
Abstract: Malaria treatment with ACTs (Artemisinin-based Combination Therapies), combining a chemical derivative of artemisinin, and a partner drug has, for more than 15 years, produced a notable decrease in the mortality in tropical and subtropical areas. However, since 2008, a serious threat has emerged in western Cambodia, where the clinical efficacy of artemisinins has significantly declined, with a delayed parasite clearance rate and high recrudescence rates in the following weeks. Resistance of Plasmodium to artemisinins is now reported in several countries in South-East Asia. ACTs remain effective as long as the partner drug retains its activity but more and more clinical failures related to parasite resistance to both resistant parasites in sub-Saharan Africa, the continent most affected by malaria, as was the case in the past with other antimalarial treatments. It is therefore essential to better understand, from phenotypic and genotypic points of view, the mechanisms of resistance developed by the parasite Plasmodium falciparum face artemisinin and its derivatives in order to offer new therapeutic tools.
Published: 2016
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23. Multiple phenotypic and genotypic artemisinin sensitivity evaluation of Malian Plasmodium falciparum isolates

Author: Sandie Menard, Antoine Berry, Françoise Benoit-Vical, Pety Tor, Arba Pramundita Ramadani, Antoine Dara, Jean-Michel Augereau, Karamoko Niaré, Ogobara K. Doumbo, Lucie Paloque, Malaria Research and Training Center [Bamako, Mali], Université de Bamako, Laboratoire de chimie de coordination (LCC), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées, Centre de Physiopathologie Toulouse Purpan (CPTP), 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), Division of Malaria Research, Institute for Global Health, University of Maryland School of Medicine, University of Maryland School of Medicine, University of Maryland System-University of Maryland System, Service de Parasitologie et Mycologie, CHU Toulouse [Toulouse]-Institut Fédératif de Biologie (IFB) - Hôpital Purpan, Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Centre de Physiopathologie Toulouse Purpan ex IFR 30 et IFR 150 (CPTP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Service de Parasitologie-Mycologie [Toulouse], and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse]
Subjects: 0301 basic medicine, Genotype, medicine.medical_treatment, Plasmodium falciparum, 030106 microbiology, 030231 tropical medicine, Drug Resistance, Dihydroartemisinin, Drug resistance, Microbiology, Antimalarials, 03 medical and health sciences, 0302 clinical medicine, Gentamicin protection assay, Virology, parasitic diseases, medicine, Humans, Parasite hosting, [CHIM.COOR]Chemical Sciences/Coordination chemistry, Artemisinin, ComputingMilieux_MISCELLANEOUS, biology, Articles, biology.organism_classification, Artemisinins, 3. Good health, Phenotype, Infectious Diseases, Parasitology, Ex vivo, medicine.drug
Abstract: International audience; We assessed the ex vivo/in vitro sensitivity of 54 Malian Plasmodium falciparum isolates to artemisinin for the monitoring of drug resistance in this area. The artemisinin sensitivity of parasites was evaluated using 1) the ex vivo and in vitro parasite recrudescence detection after treatment of the ring stage with 1–200 nM artemisinin for 48 hours and 2) the in vitro parasite recrudescence kinetics assay over 7 days after 6-hour treatment of the ring stage with 700 nM dihydroartemisinin (DHA). In addition, as recommended by the World Health Organization for artemisinin resistance characterization, the ring-stage survival assay (RSA0–3 h) was performed and the parasite isolates were sequenced at the kelch 13 propeller locus. No clinical and molecular evidence of artemisinin resistance was observed. However, these isolates present different phenotypic profiles in response to artemisinin treatments. Despite all RSA0–3 h values less than 1.5%, six out of 46 (13.0%) isolates tested ex vivo and four out of six (66.7%) isolates tested in vitro were able to multiply after 48-hour treatments with 100 nM artemisinin. Moreover, five out of eight isolates tested showed faster parasite recovery after DHA treatment in kinetic assays. The presence of such phenotypes needs to be taken into account in the assessment of the efficacy of artemisinins in Mali. The assays presented here appear as valuable tools for the monitoring of artemisinin sensitivity in the field and thus could help to evaluate the risk of emergence of artemisinin resistance in Africa.
Published: 2018
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24. Investigation of Artemisinin Sensitivity with Alternative ex vivo/in vitro Assays in Mali

Author: Karamoko Niaré, Paloque, Lucie, Menard, Sandie, Tor, Pety, Ramadani, Arba Pramundita, Jean-Michel Augereau, Dara, Antoine, Berry, Antoine, Benoit-Vical, Françoise, and Ogobara K Doumbo
Published: 2018
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25. Plasmodium falciparum resistance to artemisinin-based combination therapies: A sword of Damocles in the path toward malaria elimination

Author: Lucie Paloque, Françoise Benoit-Vical, Jean-Michel Augereau, Manel Ouji, Laboratoire de chimie de coordination (LCC), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut de Chimie de Toulouse (ICT), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), and ANR-16-CE35-0003,INMAR,Réseau intégré des mécanismes de quiescence & clairance impliqués dans la résistance à l'artémisinine chez Plasmodium(2016)
Subjects: 0301 basic medicine, Artemisinins, Asia, Veterinary (miscellaneous), 030231 tropical medicine, 030106 microbiology, Plasmodium falciparum, malaria, Drug resistance, Review Article, Biology, lcsh:Infectious and parasitic diseases, 03 medical and health sciences, Antimalarials, 0302 clinical medicine, Pharmacotherapy, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Malaria elimination, parasitic diseases, medicine, Humans, lcsh:RC109-216, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, Artemisinin, Disease Eradication, Malaria, Falciparum, Africa South of the Sahara, Asia, Southeastern, Clinical Trials as Topic, drug resistance, Resistance (ecology), biology.organism_classification, medicine.disease, Virology, Drug Resistance, Multiple, 3. Good health, Parasite, Infectious Diseases, artemisinin, Insect Science, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Animal Science and Zoology, Parasitology, Drug Therapy, Combination, Cambodia, Malaria, medicine.drug
Abstract: The use of artemisinin-based combination therapies (ACTs), which combine an artemisinin derivative with a partner drug, in the treatment of uncomplicated malaria has largely been responsible for the significant reduction in malaria-related mortality in tropical and subtropical regions. ACTs have also played a significant role in the 18% decline in the incidence of malaria cases from 2010 to 2016. However, this progress is seriously threatened by the reduced clinical efficacy of artemisinins, which is characterised by delayed parasitic clearance and a high rate of recrudescence, as reported in 2008 in Western Cambodia. Resistance to artemisinins has already spread to several countries in Southeast Asia. Furthermore, resistance to partner drugs has been shown in some instances to be facilitated by pre-existing decreased susceptibility to the artemisinin component of the ACT. A major concern is not only the spread of these multidrug-resistant parasites to the rest of Asia but also their possible appearance in Sub-Saharan Africa, the continent most affected by malaria, as has been the case in the past with parasite resistance to other antimalarial treatments. It is therefore essential to understand the acquisition of resistance to artemisinins by Plasmodium falciparum to adapt malaria treatment policies and to propose new therapeutic solutions.Résistance de Plasmodium falciparum aux combinaisons thérapeutiques à base d’artémisinine : une épée de Damoclès sur les stratégies d’éradication du paludisme.L’utilisation, dans le traitement du paludisme simple, de combinaisons thérapeutiques associant un dérivé de l’artémisinine et une molécule partenaire a largement contribué à une réduction significative de la mortalité due à cette pathologie dans les régions tropicales et subtropicales ainsi qu’une diminution de 18% de nombre de cas de 2010 à 2016. Cependant, ces progrès sont sérieusement menacés par la diminution de l’efficacité clinique des artémisinines caractérisées par des clairances parasitaires retardées et un taux de recrudescence élevé, signalés en 2008 à l’ouest du Cambodge. La résistance aux artémisinines s’est déjà étendue à plusieurs pays d’Asie du Sud-Est. De plus, il a été montré que la résistance aux molécules partenaires des artémisinines dans ces combinaisons thérapeutiques (ACT) a été facilitée suite à une diminution de la sensibilité à l’artémisinine. L’une des principales préoccupations est non seulement la propagation de ces parasites multi-résistants dans le reste de l’Asie, mais aussi leur apparition possible en Afrique subsaharienne, continent le plus touché par le paludisme, comme cela a été le cas dans le passé avec la résistance de parasites à d’autres traitements antipaludiques. Il est donc essentiel de comprendre l’acquisition de la résistance de Plasmodium falciparum aux artémisinines afin d’adapter les politiques de santé face au paludisme et de proposer de nouvelles solutions thérapeutiques.
Published: 2018
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26. Endoperoxide-based compounds: cross-resistance with artemisinins and selection of a Plasmodium falciparum lineage with a K13 non-synonymous polymorphism

Author: Françoise Benoit-Vical, Anne Robert, Jean-Michel Augereau, Manel Ouji, Joël Lelièvre, Lucie Paloque, Didier Menard, Tanila Ben Haddou, Frédéric Ariey, Bernard Meunier, Benoit Witkowski, Laboratoire de chimie de coordination (LCC), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées, Malaria Molecular Epidemiology, Institut Pasteur du Cambodge, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5), Service de parasitologie-mycologie [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Cochin [AP-HP], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Cochin [AP-HP], and CHU Cochin [AP-HP]
Subjects: 0301 basic medicine, Microbiology (medical), Drug, Artemisinins, Genotype, media_common.quotation_subject, 030106 microbiology, Plasmodium falciparum, Drug Resistance, Protozoan Proteins, Drug resistance, 03 medical and health sciences, Antimalarials, Parasitic Sensitivity Tests, parasitic diseases, medicine, Humans, Pharmacology (medical), [CHIM.COOR]Chemical Sciences/Coordination chemistry, Artemisinin, Malaria, Falciparum, Selection, Genetic, Cross-resistance, media_common, Pharmacology, Genetics, biology, Whole Genome Sequencing, medicine.disease, biology.organism_classification, 3. Good health, Infectious Diseases, Phenotype, Mutant Proteins, Cambodia, Malaria, medicine.drug
Abstract: International audience; Background: Owing to the emergence of multiresistant Plasmodium falciparum parasites in Southeast Asia, along with the impressive decrease in the efficacy of the endoperoxide compound artemisinin and of artemisinin-based combination therapies, the development of novel antimalarial drugs or combinations is required. Although several antiplasmodial molecules, such as endoperoxide-based compounds, are in advanced research or development, we do not know whether resistance to artemisinin derivatives might impact the efficacy of these new compounds. Objectives: To address this issue, the antiplasmodial efficacy of trioxaquines, hybrid endoperoxide-based molecules, was explored, along with their ability to select in vitro resistant parasites under discontinuous and dose-escalating drug pressure. Methods: The in vitro susceptibilities of artemisinin- and trioxaquine-resistant laboratory strains and recent Cambodian field isolates were evaluated by different phenotypic and genotypic assays. Results: Trioxaquines tested presented strong cross-resistance with artemisinin both in the artemisinin-resistant laboratory F32-ART5 line and in Cambodian field isolates. Trioxaquine drug pressure over 4 years led to the in vitro selection of the F32-DU line, which is resistant to trioxaquine and artemisinin, similar to the F32-ART lineage. F32-DU whole genome sequencing (WGS) revealed that resistance to trioxaquine was associated with the same non-synonymous mutation in the propeller domain of the K13 protein (M476I) that was found in the F32-ART lineage. Conclusions : These worrisome results indicate the risk of cross-resistance between artemisinins and endoperoxide-based antiplasmodial drugs in the development of the K13 mutant parasites and question the usefulness of these molecules in the future therapeutic arsenal.
Published: 2017
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27. Plasmodium falciparum: multifaceted resistance to artemisinins

Author: Arba Pramundita Ramadani, Jean-Michel Augereau, Françoise Benoit-Vical, Odile Mercereau-Puijalon, Lucie Paloque, Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées, Laboratoire de chimie de coordination (LCC), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Immunologie moléculaire des parasites, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), ANR-13-BSV3-0018,MALARTRES,Résistance de Plasmodium aux antipaludiques de la famille des artémisinines(2013), ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), BMC, BMC, Blanc 2013 - Résistance de Plasmodium aux antipaludiques de la famille des artémisinines - - MALARTRES2013 - ANR-13-BSV3-0018 - Blanc 2013 - VALID, Integrative Biology of Emerging Infectious Diseases - - IBEID2010 - ANR-10-LABX-0062 - LABX - VALID, Institut de Chimie de Toulouse (ICT-FR 2599), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Université de Toulouse (UT), Institut de Chimie de Toulouse (ICT), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), and Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, Artemisinins, [SDV]Life Sciences [q-bio], Plasmodium falciparum, Resistance, Drug Resistance, Review, Drug resistance, Biology, Quiescence, Models, Biological, Antimalarials, 03 medical and health sciences, parasitic diseases, medicine, Humans, Malaria, Falciparum, [SDV.MP] Life Sciences [q-bio]/Microbiology and Parasitology, Transcription factor, PI3K/AKT/mTOR pathway, Apicoplast, PfK13, biology.organism_classification, medicine.disease, Virology, Artemisinin-based combination therapy, 3. Good health, Cell biology, Malaria, [SDV] Life Sciences [q-bio], 030104 developmental biology, Infectious Diseases, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Unfolded protein response, Parasitology
Abstract: Plasmodium falciparum resistance to artemisinins, the most potent and fastest acting anti-malarials, threatens malaria elimination strategies. Artemisinin resistance is due to mutation of the PfK13 propeller domain and involves an unconventional mechanism based on a quiescence state leading to parasite recrudescence as soon as drug pressure is removed. The enhanced P. falciparum quiescence capacity of artemisinin-resistant parasites results from an increased ability to manage oxidative damage and an altered cell cycle gene regulation within a complex network involving the unfolded protein response, the PI3K/PI3P/AKT pathway, the PfPK4/eIF2α cascade and yet unidentified transcription factor(s), with minimal energetic requirements and fatty acid metabolism maintained in the mitochondrion and apicoplast. The detailed study of these mechanisms offers a way forward for identifying future intervention targets to fend off established artemisinin resistance. Electronic supplementary material The online version of this article (doi:10.1186/s12936-016-1206-9) contains supplementary material, which is available to authorized users.
Published: 2016
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28. Antiplasmodial activities of gold(I) complexes involving functionalized N-heterocyclic carbenes

Author: Heinz Gornitzka, Luca Boselli, Álvaro Fernández Álvarez, Jean-Michel Augereau, Françoise Benoit-Vical, Arba Pramundita Ramadani, Catherine Hemmert, Lucie Paloque, Laboratoire de chimie de coordination (LCC), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Universitas Gadjah Mada, Service de Parasitologie et Mycologie, CHU Toulouse [Toulouse]-Institut Fédératif de Biologie (IFB) - Hôpital Purpan, Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Institut de Chimie de Toulouse (ICT), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Service de Parasitologie et Mycologie [CHU Toulouse], Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Biologie [CHU Toulouse], and Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)
Subjects: Stereochemistry, Cell Survival, Clinical Biochemistry, Plasmodium falciparum, Pharmaceutical Science, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, 010402 general chemistry, Crystallography, X-Ray, 01 natural sciences, Biochemistry, Medicinal chemistry, Antimalarials, Inhibitory Concentration 50, Structure-Activity Relationship, Drug Discovery, Chlorocebus aethiops, Organometallic Compounds, Molecule, Animals, [CHIM.COOR]Chemical Sciences/Coordination chemistry, Cytotoxicity, Molecular Biology, Vero Cells, biology, Molecular Structure, 010405 organic chemistry, Chemistry, Organic Chemistry, Cationic polymerization, Chloroquine, biology.organism_classification, In vitro, 0104 chemical sciences, Lipophilicity, Molecular Medicine, Gold, Selectivity, Methane
Abstract: International audience; A series of twenty five molecules, including imidazolium salts functionalized by N-, O- or S-containing groups and their corresponding cationic, neutral or anionic gold(I) complexes were evaluated on Plasmodium falciparum in vitro and then on Vero cells to determine their selectivity. Among them, eight new compounds were synthesized and fully characterized by spectroscopic methods. The X-ray structures of three gold(I) complexes are presented. Except one complex (18), all the cationic gold(I) complexes show potent antiplasmodial activity with IC50 in the micro-and submicromolar range, correlated with their lipophilicity. Structure-activity relationships enable to evidence a lead-complex (21) displaying a good activity (IC50 = 210 nM) close to the value obtained with chloroquine (IC50 = 514 nM) and a weak cytotoxicity.
Published: 2016
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29. Conservation de souches de cellules végétales productrices de métabolites

Author: Jean-Michel Augereau, Vincent Petiard, and Didier Courtois
Subjects: Chemistry, General Medicine, Molecular biology
Abstract: ResumeLa conservation a long terme de cultures de cellules vegetales productrices de metabolites a deux objectifs principaux: 1 Eviter des modifications de souches pouvant etre dues a une evolution du degre de ploidie, a des mutations ou a des variations epigenetiques.2 Diminuer les risques de contaminations et alleger les charges de travail que represente le repiquage regulier des souches. Deux voies sont envisageables: ralentir ou bien arreter la croissance des tissus.Les techniques de croissance ralentie sont principalement representees par le stockage des tissus a des temperatures relativement basses non gelantes (de 4°C a 15°C) et par l'hypoxie sous une couche d'huile de paraffine.L'arret de la croissance des tissus et du metabolisme cellulaire dans son ensemble est essentiellement obtenu par la conservation des cellules dans l'azote liquide a—196°C.Si ces trois techniques se sont revelees efficaces pour la conservation du phenotype de plusieurs souches, aucune a ce jour n'est cependant «universelle»...
Published: 1986
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30. MOESM1 of Plasmodium falciparum: multifaceted resistance to artemisinins

Author: Paloque, Lucie, Ramadani, Arba, Mercereau-Puijalon, Odile, Jean-Michel Augereau, and Franรงoise Benoit-Vical
Subjects: 3. Good health
Abstract: Additional file 1. ACT recommended by WHO and the newly approved combination DHA-piperaquine.

31. MOESM1 of Plasmodium falciparum: multifaceted resistance to artemisinins

Author: Paloque, Lucie, Ramadani, Arba, Mercereau-Puijalon, Odile, Jean-Michel Augereau, and Franรงoise Benoit-Vical
Subjects: 3. Good health
Abstract: Additional file 1. ACT recommended by WHO and the newly approved combination DHA-piperaquine.

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31 results on '"Jean-Michel Augereau"'

1. In artemisinin-resistant falciparum malaria parasites, mitochondrial metabolic pathways are essential for survival but not those of apicoplast

2. Epigenetic regulation as a therapeutic target in the malaria parasite Plasmodium falciparum

3. Peptide-Alkoxyamine Drugs: An Innovative Approach to Fight Schistosomiasis: 'Digging Their Graves with Their Forks'

4. Hybrid Peptide-Alkoxyamine Drugs: A Strategy for the Development of a New Family of Antiplasmodial Drugs

5. Epidrugs as Promising Tools to Eliminate Plasmodium falciparum Artemisinin-Resistant and Quiescent Parasites

6. Reactive Oxygen Species as the Brainbox in Malaria Treatment

7. Alkoxyamines Designed as Potential Drugs against Plasmodium and Schistosoma Parasites

8. Hybrid Gold(I) NHC-Artemether Complexes to Target Falciparum Malaria Parasites

9. An LC–MS Assay to Measure Superoxide Radicals and Hydrogen Peroxide in the Blood System

10. Young Sprague Dawley rats infected by Plasmodium berghei: A relevant experimental model to study cerebral malaria.

11. Mutation in the Plasmodium falciparum BTB/POZ Domain of K13 Protein Confers Artemisinin Resistance

12. Reactive Oxygen Species as the Brainbox in Malaria Treatment

13. Resistance to artemisinin in falciparum malaria parasites: A redox-mediated phenomenon

14. The antimalarial MMV688533 provides potential for single-dose cures with a high barrier to Plasmodium falciparum parasite resistance

15. Superoxide: A major role in the mechanism of action of essential antimalarial drugs

16. The antimalarial MMV688533 provides potential for single-dose cures with a high barrier to

17. Novel molecule combinations and corresponding hybrids targeting artemisinin-resistant Plasmodium falciparum parasites

18. Identification of compounds active against quiescent artemisinin-resistant Plasmodium falciparum parasites via the quiescent-stage survival assay (QSA)

19. Antiprotozoal properties of Indonesian medicinal plant extracts

20. Alkoxyamines Designed as Potential Drugs against Plasmodium and Schistosoma Parasites

21. [Plasmodium resistance, a brake on its eradication]

22. Résistance de l’agent du paludisme, Plasmodium falciparum aux combinaisons thérapeutiques à base d’artémisinine (ACTs) : Craintes d’une chimiorésistance généralisée

23. Multiple phenotypic and genotypic artemisinin sensitivity evaluation of Malian Plasmodium falciparum isolates

24. Investigation of Artemisinin Sensitivity with Alternative ex vivo/in vitro Assays in Mali

25. Plasmodium falciparum resistance to artemisinin-based combination therapies: A sword of Damocles in the path toward malaria elimination

26. Endoperoxide-based compounds: cross-resistance with artemisinins and selection of a Plasmodium falciparum lineage with a K13 non-synonymous polymorphism

27. Plasmodium falciparum: multifaceted resistance to artemisinins

28. Antiplasmodial activities of gold(I) complexes involving functionalized N-heterocyclic carbenes

29. Conservation de souches de cellules végétales productrices de métabolites

30. MOESM1 of Plasmodium falciparum: multifaceted resistance to artemisinins

31. MOESM1 of Plasmodium falciparum: multifaceted resistance to artemisinins

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31 results on '"Jean-Michel Augereau"'

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