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1. A lipid-binding protein mediates rhoptry discharge and invasion in Plasmodium falciparum and Toxoplasma gondii parasites

Author

Catherine Suarez, Gaëlle Lentini, Raghavendran Ramaswamy, Marjorie Maynadier, Eleonora Aquilini, Laurence Berry-Sterkers, Michael Cipriano, Allan L. Chen, Peter Bradley, Boris Striepen, Martin J. Boulanger, and Maryse Lebrun

Subjects
Science
Abstract

Plasmodium and Toxoplasma parasites rely on rhoptry exocytosis for invasion, but the underlying mechanism is not known. Here, Suarez et al. characterize rhoptry apical surface proteins (RASP) that localize to the rhoptry cap and bind charged lipids, and are essential for rhoptry secretion and invasion.

Published
2019
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2. Contribution of the precursors and interplay of the pathways in the phospholipid metabolism of the malaria parasite

Author

Sharon Wein, Salma Ghezal, Corinne Buré, Marjorie Maynadier, Christian Périgaud, Henri J. Vial, Isabelle Lefebvre-Tournier, Kai Wengelnik, and Rachel Cerdan

Subjects
Plasmodium falciparum, Kennedy pathway, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, lysophosphatidylcholine, Biochemistry, QD415-436
Abstract

The malaria parasite, Plasmodium falciparum, develops and multiplies in the human erythrocyte. It needs to synthesize considerable amounts of phospholipids (PLs), principally phosphatidylcholine (PC), phosphatidylethanolamine (PE), and phosphatidylserine (PS). Several metabolic pathways coexist for their de novo biosynthesis, involving a dozen enzymes. Given the importance of these PLs for the survival of the parasite, we sought to determine their sources and to understand the connections and dependencies between the multiple pathways. We used three deuterated precursors (choline-d9, ethanolamine-d4, and serine-d3) to follow and quantify simultaneously their incorporations in the intermediate metabolites and the final PLs by LC/MS/MS. We show that PC is mainly derived from choline, itself provided by lysophosphatidylcholine contained in the serum. In the absence of choline, the parasite is able to use both other precursors, ethanolamine and serine. PE is almost equally synthesized from ethanolamine and serine, with both precursors being able to compensate for each other. Serine incorporated in PS is mainly derived from the degradation of host cell hemoglobin by the parasite. P. falciparum thus shows an unexpected adaptability of its PL synthesis pathways in response to different disturbances. These data provide new information by mapping the importance of the PL metabolic pathways of the malaria parasite and could be used to design future therapeutic approaches.

Published
2018
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4. Rodent and nonrodent malaria parasites differ in their phospholipid metabolic pathways[S]

Author

Sandrine Déchamps, Marjorie Maynadier, Sharon Wein, Laila Gannoun-Zaki, Eric Maréchal, and Henri J. Vial

Subjects
Plasmodium falciparum, Plasmodium berghei, Plasmodium vinckei, lipid, phospholipid biosynthesis, phosphatidylcholine, Biochemistry, QD415-436
Abstract

Malaria, a disease affecting humans and other animals, is caused by a protist of the genus Plasmodium. At the intraerythrocytic stage, the parasite synthesizes a high amount of phospholipids through a bewildering number of pathways. In the human Plasmodium falciparum species, a plant-like pathway that relies on serine decarboxylase and phosphoethanolamine N-methyltransferase activities diverts host serine to provide additional phosphatidylcholine and phosphatidylethanolamine to the parasite. This feature of parasitic dependence toward its host was investigated in other Plasmodium species. In silico analyses led to the identification of phosphoethanolamine N-methyltransferase gene orthologs in primate and bird parasite genomes. However, the gene was not detected in the rodent P. berghei, P. yoelii, and P. chabaudi species. Biochemical experiments with labeled choline, ethanolamine, and serine showed marked differences in biosynthetic pathways when comparing rodent P. berghei and P. vinckei, and human P. falciparum species. Notably, in both rodent parasites, ethanolamine and serine were not significantly incorporated into phosphatidylcholine, indicating the absence of phosphoethanolamine N-methyltransferase activity. To our knowledge, this is the first study to highlight a crucial difference in phospholipid metabolism between Plasmodium species. The findings should facilitate efforts to develop more rational approaches to identify and evaluate new targets for antimalarial therapy.

Published
2010
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5. A lipid-binding protein mediates rhoptry discharge and invasion in Plasmodium falciparum and Toxoplasma gondii parasites

Author

Allan L. Chen, Marjorie Maynadier, Boris Striepen, Michael J. Cipriano, Laurence Berry-Sterkers, Catherine Suarez, Peter J. Bradley, Gaelle Lentini, Eleonora Aquilini, Martin J. Boulanger, Raghavendran Ramaswamy, and Maryse Lebrun

Subjects
0301 basic medicine, Science, Plasmodium falciparum, Protozoan Proteins, General Physics and Astronomy, 02 engineering and technology, Plasmodium, Article, Exocytosis, General Biochemistry, Genetics and Molecular Biology, Cell Line, Host-Parasite Interactions, Apicomplexa, 03 medical and health sciences, Microscopy, Electron, Transmission, parasitic diseases, Animals, Humans, Parasites, Secretion, lcsh:Science, Phospholipids, Organelles, Multidisciplinary, biology, Rhoptry, Toxoplasma gondii, General Chemistry, Fibroblasts, 021001 nanoscience & nanotechnology, biology.organism_classification, 3. Good health, Cell biology, Parasite biology, 030104 developmental biology, Microscopy, Fluorescence, Cytoplasm, lcsh:Q, Carrier Proteins, 0210 nano-technology, Toxoplasma
Abstract

Members of the Apicomplexa phylum, including Plasmodium and Toxoplasma, have two types of secretory organelles (micronemes and rhoptries) whose sequential release is essential for invasion and the intracellular lifestyle of these eukaryotes. During invasion, rhoptries inject an array of invasion and virulence factors into the cytoplasm of the host cell, but the molecular mechanism mediating rhoptry exocytosis is unknown. Here we identify a set of parasite specific proteins, termed rhoptry apical surface proteins (RASP) that cap the extremity of the rhoptry. Depletion of RASP2 results in loss of rhoptry secretion and completely blocks parasite invasion and therefore parasite proliferation in both Toxoplasma and Plasmodium. Recombinant RASP2 binds charged lipids and likely contributes to assembling the machinery that docks/primes the rhoptry to the plasma membrane prior to fusion. This study provides important mechanistic insight into a parasite specific exocytic pathway, essential for the establishment of infection., Plasmodium and Toxoplasma parasites rely on rhoptry exocytosis for invasion, but the underlying mechanism is not known. Here, Suarez et al. characterize rhoptry apical surface proteins (RASP) that localize to the rhoptry cap and bind charged lipids, and are essential for rhoptry secretion and invasion.

Published
2019

6. G-Quadruplex Identification in the Genome of Protozoan Parasites Points to Naphthalene Diimide Ligands as New Antiparasitic Agents

Author

Jose Juan Lopez-Rubio, Michela Zuffo, Juan Carlos Morales, Jean-Louis Mergny, Jenny Campos-Salinas, José M. Pérez-Victoria, Matilde Arévalo-Ruiz, Filippo Doria, Efres Belmonte-Reche, Marta Martínez-García, Mauro Freccero, Aurore Guédin, Marjorie Maynadier, Instituto de Parasitología y Biomedicina 'López Neyra', CSIC, Imagerie Moléculaire et Nanobiotechnologies - Institut Européen de Chimie et Biologie (IECB), Université Sciences et Technologies - Bordeaux 1-Centre National de la Recherche Scientifique (CNRS), University of Pavia, Dynamique des interactions membranaires normales et pathologiques (DIMNP), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université Montpellier 1 (UM1), Maladies infectieuses et vecteurs : écologie, génétique, évolution et contrôle (MIVEGEC), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud]), Institut Européen de Chimie et Biologie (IECB), Centre National de la Recherche Scientifique (CNRS)-Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Instituto de Investigaciones Químicas, CSIC

Subjects
0301 basic medicine, Antiparasitic, medicine.drug_class, [SDV]Life Sciences [q-bio], Naphthalenes, G-quadruplex, Imides, Ligands, Genome, Cell Line, 03 medical and health sciences, chemistry.chemical_compound, Drug Discovery, parasitic diseases, medicine, Animals, Humans, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, Nucleotide, Zebrafish, chemistry.chemical_classification, Regulation of gene expression, Antiparasitic Agents, Telomere, Antiparasitic agent, 3. Good health, G-Quadruplexes, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, 030104 developmental biology, Biochemistry, chemistry, Kinetoplast, Molecular Medicine, Genome, Protozoan, DNA
Abstract

G-quadruplexes (G4) are DNA secondary structures that take part in the regulation of gene expression. Putative G4 forming sequences (PQS) have been reported in mammals, yeast, bacteria, and viruses. Here, we present PQS searches on the genomes of T. brucei, L. major, and P. falciparum. We found telomeric sequences and new PQS motifs. Biophysical experiments showed that EBR1, a 29 nucleotide long highly repeated PQS in T. brucei, forms a stable G4 structure. G4 ligands based on carbohydrate conjugated naphthalene diimides (carb-NDIs) that bind G4's including hTel could bind EBR1 with selectivity versus dsDNA. These ligands showed important antiparasitic activity. IC50 values were in the nanomolar range against T. brucei with high selectivity against MRC-5 human cells. Confocal microscopy confirmed these ligands localize in the nucleus and kinetoplast of T. brucei suggesting they can reach their potential G4 targets. Cytotoxicity and zebrafish toxicity studies revealed sugar conjugation reduces intrinsic toxicity of NDIs., This work was supported by the Spanish Ministerio de Economía y Competitividad (Grants CTQ2012-35360, CTQ2015-64275-P, and SAF2016-80228-R), Junta de Andalucía (Grant BIO1786), Worldwide Cancer Research Foundation (Grant 16-0290), Italian Association for Cancer Research (AIRC, Grant IG2013-14708), Agence Nationale de la Recherche (ANR Quarpdiem, Grant ANR-12-BSV8-0008-01), the SYMBIT project (Reg. No. CZ.02.1.01/0.0/0.0/15_003/0000477) financed by the ERDF, and FEDER funds from the EU are gratefully acknowledged. M.A.-R. and M.M.-G. thank Ministerio de Educación, Cultura y Deporte for a FPU and a FPI predoctoral fellowship, respectively. E.B.-R. is a student of the pharmacy Ph.D. program of the University of Granada (Spain).

Published
2018
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7. Synthesis of an Uncharged Tetra-cyclopeptide Acting as a Transmembrane Carrier: Enhanced Cellular and Nuclear Uptake

Author

Yung-Sing Wong, Flaviane F. Hilário, Marjorie Maynadier, Vincent Zwick, Henri Vial, Rossimiriam Pereira de Freitas, Claudia A. Simões-Pires, Mohamed Dit Mady Traoré, Laurence Berry, Nicolas Fantozzi, Sharon Wein, and Muriel Cuendet

Subjects
Scaffold, Cell, Triazole, Nanotechnology, 010402 general chemistry, 01 natural sciences, Biochemistry, Peptides, Cyclic, chemistry.chemical_compound, medicine, Physical and Theoretical Chemistry, ddc:615, Natural product, biology, Molecular Structure, 010405 organic chemistry, Organic Chemistry, Cell Membrane, biology.organism_classification, Fluorescence, Transmembrane protein, 0104 chemical sciences, Membrane, medicine.anatomical_structure, chemistry, Biophysics, Tetra
Abstract

A small uncharged cyclopeptide scaffold inspired by a natural product and designed to undergo postfunctionalizations was used as a new transmembrane vector. A bioactive and fluorescent triazole aminocoumarin was bound to this carrier to facilitate its moving across cell and subcellular membranes, and this led to an increase in its cell toxicity.

Published
2017

8. Transport and pharmacodynamics of albitiazolium, an antimalarial drug candidate

Author

P Bette-Bobillo, Laurent Fraisse, Sharon Wein, Diana Marcela Penarete-Vargas, Sweta Maheshwari, Marjorie Maynadier, Henri Vial, Rachel Cerdan, Julie Perez, Yann Bordat, and C Tran Van Ba

Subjects
drug transport, Plasmodium, Erythrocytes, Plasmodium falciparum, phospholipid synthesis, malaria, Pharmacology, Biology, Choline, lipids, 03 medical and health sciences, chemistry.chemical_compound, Antimalarials, Biosynthesis, In vivo, Phosphatidylcholine, medicine, Animals, Humans, 030304 developmental biology, chemistry.chemical_classification, 0303 health sciences, therapy, Molecular Structure, 030306 microbiology, Transporter, Biological Transport, Research Papers, 3. Good health, De novo synthesis, Thiazoles, Enzyme, Mechanism of action, chemistry, Biochemistry, Phosphatidylcholines, medicine.symptom
Abstract

BACKGROUND AND PURPOSE Choline analogues, a new type of antimalarials, exert potent in vitro and in vivo antimalarial activity. This has given rise to albitiazolium, which is currently in phase II clinical trials to cure severe malaria. Here we dissected its mechanism of action step by step from choline entry into the infected erythrocyte to its effect on phosphatidylcholine (PC) biosynthesis. EXPERIMENTAL APPROACH We biochemically unravelled the transport and enzymatic steps that mediate de novo synthesis of PC and elucidated how albitiazolium enters the intracellular parasites and affects the PC biosynthesis. KEY RESULTS Choline entry into Plasmodium falciparum-infected erythrocytes is achieved both by the remnant erythrocyte choline carrier and by parasite-induced new permeability pathways (NPP), while parasite entry involves a poly-specific cation transporter. Albitiazolium specifically prevented choline incorporation into its end-product PC, and its antimalarial activity was strongly antagonized by choline. Albitiazolium entered the infected erythrocyte mainly via a furosemide-sensitive NPP and was transported into the parasite by a poly-specific cation carrier. Albitiazolium competitively inhibited choline entry via the parasite-derived cation transporter and also, at a much higher concentration, affected each of the three enzymes conducting de novo synthesis of PC. CONCLUSIONS AND IMPLICATIONS Inhibition of choline entry into the parasite appears to be the primary mechanism by which albitiazolium exerts its potent antimalarial effect. However, the pharmacological response to albitiazolium involves molecular interactions with different steps of the de novo PC biosynthesis pathway, which would help to delay the development of resistance to this drug.

Published
2012
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9. Design, synthesis and evaluation of new tricyclic endoperoxides as potential antiplasmodial agents

Author

Marjorie Maynadier, Henri Vial, Christiane André-Barrès, Sonia Mallet-Ladeira, Jérémy Ruiz, Laboratoire de Mathématiques Blaise Pascal (LMBP), Université Blaise Pascal - Clermont-Ferrand 2 (UBP)-Centre National de la Recherche Scientifique (CNRS), 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), Dynamique des interactions membranaires normales et pathologiques (DIMNP), Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Dynamique moléculaire des interactions membranaires (DMIM), Centre National de la Recherche Scientifique (CNRS)-Université Montpellier 2 - Sciences et Techniques (UM2), Synthèse et Physico-Chimie de Molécules d'Intérêt Biologique (SPCMIB), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-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), Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), 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
Erythrocytes, Free Radicals, Stereochemistry, Iron, Plasmodium falciparum, 010402 general chemistry, Tritium, 01 natural sciences, Biochemistry, Peroxide, chemistry.chemical_compound, Antimalarials, Inhibitory Concentration 50, parasitic diseases, Molecule, Moiety, Humans, [CHIM]Chemical Sciences, Physical and Theoretical Chemistry, ComputingMilieux_MISCELLANEOUS, chemistry.chemical_classification, Hypoxanthine, biology, Autoxidation, 010405 organic chemistry, Organic Chemistry, Chloroquine, biology.organism_classification, Combinatorial chemistry, Artemisinins, 0104 chemical sciences, 3. Good health, Peroxides, chemistry, Design synthesis, Drug Design, Aminoquinolines, In vitro growth, Oxidation-Reduction, Tricyclic
Abstract

Diastereoselective autoxidation allowed preparation of new tricyclic endoperoxides. These compounds and their methylated analogs were evaluated against the in vitro growth of Plasmodium falciparum, the malaria-causing parasite, showing moderate activities. However, hybrid molecules composed of the tricyclic peroxide moiety and 7-chloro-4-aminoquinoline were synthesized and displayed a marked increase in antiplasmodial activity.

Published
2014
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10. Synthesis and antiplasmodial evaluation of cyclopropyl analogs of the G-factor bicyclic peroxide

Author

Henri Vial, Robert Lauricella, Jérémy Ruiz, Christiane André-Barrès, Béatrice Tuccio, Marjorie Maynadier, Laboratoire de Mathématiques Blaise Pascal (LMBP), Université Blaise Pascal - Clermont-Ferrand 2 (UBP)-Centre National de la Recherche Scientifique (CNRS), Institut de Chimie Radicalaire (ICR), Aix Marseille Université (AMU)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Chimie, biologie et radicaux libres - UMR 6517 (CBRL), Université de la Méditerranée - Aix-Marseille 2-Université Paul Cézanne - Aix-Marseille 3-Université de Provence - Aix-Marseille 1-Centre National de la Recherche Scientifique (CNRS), Dynamique des interactions membranaires normales et pathologiques (DIMNP), Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Synthèse et Physico-Chimie de Molécules d'Intérêt Biologique (SPCMIB), 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 Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), 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), and Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Autoxidation, Bicyclic molecule, biology, 010405 organic chemistry, Stereochemistry, Organic Chemistry, Plasmodium falciparum, 010402 general chemistry, biology.organism_classification, 01 natural sciences, Biochemistry, Peroxide, 0104 chemical sciences, chemistry.chemical_compound, chemistry, Polymerization, Drug Discovery, [CHIM]Chemical Sciences, Mode of action, ComputingMilieux_MISCELLANEOUS
Abstract

New bicyclic peroxyketal comprising cyclopropyl moieties, analogs of the G3-factor, have been synthesized and evaluated against Plasmodium falciparum . They exhibit modest antimalarial activities. In order to investigate their mode of action, Fe(II) induced reduction was managed allowing us to establish mechanisms involved on the basis of the structure of the final products. Self-quenching and polymerization seem to be the major degradation ways.

Published
2013
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11. Reverse-benzamidine antimalarial agents : Design, synthesis, and biological evaluation

Author

Siham El Fangour, Roger Escale, Marjorie Maynadier, Thierry Durand, Jean-Frédéric Duckert, Henri Vial, Sharon Wein, Yen Vo-Hoang, Olivier Berger, Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM), Dynamique des interactions membranaires normales et pathologiques (DIMNP), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université Montpellier 1 (UM1), Dynamique moléculaire des interactions membranaires (DMIM), and Centre National de la Recherche Scientifique (CNRS)-Université Montpellier 2 - Sciences et Techniques (UM2)

Subjects
Reverse-benzamidines, Total clearance of parasitemia, Stereochemistry, Plasmodium falciparum, Clinical Biochemistry, Pharmaceutical Science, 01 natural sciences, Biochemistry, Chemical synthesis, Benzamidine, Antimalarial agents, Amidine, Antimalarials, Structure-Activity Relationship, 03 medical and health sciences, chemistry.chemical_compound, Drug Discovery, Structure–activity relationship, Antimalarial Agent, Molecular Biology, Chemical design, 030304 developmental biology, 0303 health sciences, 010405 organic chemistry, [CHIM.ORGA]Chemical Sciences/Organic chemistry, Organic Chemistry, Biological activity, Bis-N-akylamidines, Combinatorial chemistry, Benzamidines, 3. Good health, 0104 chemical sciences, chemistry, Drug development, Drug Design, Lipophilicity, Molecular Medicine
Abstract

International audience; In the frame of the development of bis-cationic choline analogs, the RSA of bis-N-alkylamidines were studied and a new series of reverse-benzamidine derivatives was designed. Contrary to the lipophilicity, the basicity of alkylamidine compounds directly influences their antimalarial potencies.

Published
2010
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12. Rodent and nonrodent malaria parasites differ in their phospholipid metabolic pathways

Author

Henri Vial, Sandrine Déchamps, Eric Maréchal, Marjorie Maynadier, Sharon Wein, Laila Gannoun-Zaki, Dynamique des interactions membranaires normales et pathologiques (DIMNP), Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Dynamique moléculaire des interactions membranaires (DMIM), Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), Université de Montpellier (UM), Laboratoire de physiologie cellulaire végétale (LPCV), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Recherche Agronomique (INRA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université Montpellier 1 (UM1), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Recherche Agronomique (INRA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)

Subjects
MESH: Signal Transduction, Plasmodium, Plasmodium vinckei, Plasmodium berghei, Phosphatidylethanolamine N-Methyltransferase, MESH: Amino Acid Sequence, Biochemistry, Serine, chemistry.chemical_compound, Mice, Endocrinology, MESH: Animals, MESH: Phylogeny, Phylogeny, 0303 health sciences, biology, 030302 biochemistry & molecular biology, Phosphatidylserine, 3. Good health, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Phosphatidylethanolamine N-methyltransferase, Phosphatidylcholines, Female, serine decarboxylase, Metabolic Networks and Pathways, Research Article, Signal Transduction, phosphatidylserine, Plasmodium falciparum, Molecular Sequence Data, MESH: Malaria, malaria, MESH: Sequence Alignment, MESH: Phosphatidylethanolamines, QD415-436, 03 medical and health sciences, lipid, parasitic diseases, SDV:BBM, Animals, huma parasite, metabolism, phospholipid, biosynthesis, metabolic pathway, phosphatidylcholine, phosphatidylethanolamine, enzyme, phosphoethanolamine N-methyltransferase, Amino Acid Sequence, Malaria, Phosphatidylethanolamines, Sequence Alignment, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Serine, MESH: Mice, 030304 developmental biology, Phosphatidylethanolamine, MESH: Molecular Sequence Data, MESH: Plasmodium, Cell Biology, MESH: Phosphatidylcholines, biology.organism_classification, chemistry, MESH: Metabolic Networks and Pathways, MESH: Phosphatidylethanolamine N-Methyltransferase, phospholipid biosynthesis, MESH: Female
Abstract

International audience; Malaria, a disease affecting humans and other animals, is caused by a protist of the genus Plasmodium. At the intraerythrocytic stage, the parasite synthesizes a high amount of phospholipids through a bewildering number of pathways. In the human Plasmodium falciparum species, a plant-like pathway that relies on serine decarboxylase and phosphoethanolamine N-methyltransferase activities diverts host serine to provide additional phosphatidylcholine and phosphatidylethanolamine to the parasite. This feature of parasitic dependence toward its host was investigated in other Plasmodium species. In silico analyses led to the identification of phosphoethanolamine N-methyltransferase gene orthologs in primate and bird parasite genomes. However, the gene was not detected in the rodent P. berghei, P. yoelii, and P. chabaudi species. Biochemical experiments with labeled choline, ethanolamine, and serine showed marked differences in biosynthetic pathways when comparing rodent P. berghei and P. vinckei, and human P. falciparum species. Notably, in both rodent parasites, ethanolamine and serine were not significantly incorporated into phosphatidylcholine, indicating the absence of phosphoethanolamine N-methyltransferase activity. To our knowledge, this is the first study to highlight a crucial difference in phospholipid metabolism between Plasmodium species. The findings should facilitate efforts to develop more rational approaches to identify and evaluate new targets for antimalarial therapy.

Published
2009
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13. Mono- and Bis-Thiazolium Salts Have Potent Antimalarial Activity

Author

Michèle Calas, Marjorie Maynadier, Eric Rubi, Abdallah Hamze, Henri Vial, Carole Carcel, Michel Boisbrun, Pascal Arnal, Xavier J. Salom-Roig, Sharon Wein, Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), and Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Plasmodium vinckei, Stereochemistry, Plasmodium falciparum, 010402 general chemistry, 01 natural sciences, Chemical synthesis, Antimalarials, Mice, Structure-Activity Relationship, chemistry.chemical_compound, In vivo, Drug Discovery, parasitic diseases, Animals, Choline, biology, 010405 organic chemistry, [CHIM.ORGA]Chemical Sciences/Organic chemistry, Cationic polymerization, Biological activity, biology.organism_classification, In vitro, Malaria, 0104 chemical sciences, 3. Good health, Thiazoles, chemistry, Molecular Medicine, Female
Abstract

International audience; Three new series comprising 24 novel cationic choline analogues and consisting of mono-or bis (N or C-5-duplicated) thiazolium salts have been synthesized. Bis-thiazolium salts showed potent antimalarial activity (much superior to monothiazoliums). Among them, bis-thiazolium salts 12 and 13 exhibited IC 50 values of 2.25 nM and 0.65 nM, respectively, against P. falciparum in vitro. These compounds also demonstrated good in vivo activity (ED 50 e 0.22 mg/kg), and low toxicity in mice infected by Plasmodium vinckei.

Published
2005
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