dimnp

Team Plasmodium and Toxoplasma: membrane biogenesis and host cell–parasite interactions


The phospholipid metabolism in the malaria parasite.
Group leader: Rachel Cerdan

Our research is devoted to lipid metabolism and membrane biogenesis, which that are major and essential elements for the development and differentiation of the malaria parasite, Plasmodium falciparum.

Team

CERDAN Rachel

Professor UM

rachel.cerdan -at- umontpellier.fr

WENGELNIK Kai CR INSERM kai.wengelnik -at- umontpellier.fr

WEIN Sharon

IE CNRS

sharon.wein-gratraud -at- umontpellier.fr

DUCLOVEL Coralie PhD coralie.duclovel -at- umontpellier.fr
  -- to be recruted -- PhD  
  -- to be recruted -- Postdoc  

 

                                                                             Open postdoc position pdf 

 

 Lipids are crucial for the development of the intracellular malaria parasite. The spirit of our approach is to combine biochemical, lipidomic, genetic, cellular and structural characterization of the malaria lipid metabolism, with the aim to identify particular functions in Plasmodium membrane neogenesis, cellular trafficking and signalling.

• Our programs are geared towards the functional characterization of molecular and cellular events that lead to membrane biogenesis during the development of Plasmodium parasites within host cells. The objectives are to characterize processes that are major and/or essential for the differentiation and development of these parasites, and to identify original features in these biological processes in comparison with mammalian cells. We have performed the functional analysis of the malarial lipid metabolism and phospholipid signalling using genetic and chemical manipulations. In addition we decipher the transcriptome and the metabolome linked to this metabolism to reveal the underlying regulatory networks in Plasmodium.

• As a consequence of our fundamental studies on lipid functions in Plasmodium, we have established new concepts for the development of new pharmacological approaches for antiparasitic drugs (discovery, development and mechanism of action). We design compounds that disturb the acquisition machinery and thus prevent parasite multiplication in the host.

• We have proposed a clinical candidate named Albitiazolium. This drug belongs to an exciting new class of antimalarials  currently in phase 2 clinical trials.

• We have identified other phospholipid-related transporters and enzymes that are suitable for pharmacological targeting.

We now wish to capitalise on our diverse and complementary strengths to elucidate the regulation of the Plasmodium phospholipid metabolism network and to characterize additional antimalarial targets. Our research is organised around the 4 following orientations:

Axe 1 Deciphering the phospholipid metabolism. PI: Rachel Cerdan

Axe 2 Research and development of antimalarial molecules by structure-based rational drug design. PI: Rachel Cerdan

Axe 3 Evaluation of the antimalarial potential of new compounds. PI: Sharon Wein, Rachel Cerdan

Axe 4 Understanding phosphoinositide functions in Plasmodium biology.  PI: Kai Wengelnik

 

Publication List:

2018

Ma, S., Cahalan, S., LaMonte, G., Grubaugh, N.D., Zeng, W., Murthy, S.E., Paytas, E., Gamini, R., Lukacs, V., Whitwam, T., Loud, M., Lohia, R., Berry, L., Khan, S.M., Janse, C.J., Bandell, M., Schmedt, C., Wengelnik, K., Su, A.I., Honore, E., Winzeler, E.A., Andersen, K.G., Patapoutian, A.
Common PIEZO1 Allele in African Populations Causes RBC Dehydration and Attenuates Plasmodium Infection.
Cell, 2018, 173, 443-455 e412.

Andreadaki, M., Hanssen, E., Deligianni, E., Claudet, C., Wengelnik, K., Mollard, V., McFadden, G.I., Abkarian, M., Braun-Breton, C., Siden-Kiamos, I. Sequential Membrane Rupture and Vesiculation during Plasmodium berghei Gametocyte Egress from the Red Blood Cell.
Sci. Rep., 2018, 8, 3543.

Wengelnik, K., Daher, W., Lebrun, M.
Phosphoinositides and their functions in apicomplexan parasites.
Int. J. Parasitol., 2018, 48, 493-504. Review

Wein, S., Ghezal, S., Bure, C., Maynadier, M., Perigaud, C., Vial, H.J., Lefebvre-Tournier, I., Wengelnik, K., Cerdan, R.
Contribution of the precursors and interplay of the pathways in the phospholipid metabolism of the malaria parasite.
J Lipid Res., 2018, 59, 1461-1471.

Guca, E., Nagy, G. N., Hajdu, F., Marton, L., Izrael, R., Hoh, F., Yang, Y., Vial, H., Vertessy, B. G., Guichou, J. F., and Cerdan R.
Structural determinants of the catalytic mechanism of Plasmodium CCT, a key enzyme of malaria lipid biosynthesis.
Sci. Rep., 2018, 8, 11215, 2018. doi: 10.1038/s41598-018-29500-9

2017

Wein, S., Taudon, N., Maynadier, M., Tran Van Ba, C., Margout, D., Bordat, Y., Fraisse, L., Wengelnik, K., Cerdan, R., Bressolle-Gomeni, F., Vial, H.J.
High Accumulation and In Vivo Recycling of the New Antimalarial Albitiazolium Lead to Rapid Parasite Death.
Antimicrob. Agents Chemother., 2017, 61.(8). pii: e00352-17

Bushell, E., Gomes, A.R., Sanderson, T., Anar, B., Girling, G., Herd, C., Metcalf, T., Modrzynska, K., Schwach, F., Martin, R.E., Mather, M.W., McFadden, G.I., Parts, L., Rutledge, G.G., Vaidya, A.B., Wengelnik, K., Rayner, J.C., Billker, O.
Functional Profiling of a Plasmodium Genome Reveals an Abundance of Essential Genes.
Cell, 2017, 170, 260-272 e268.

Francisco Hilario F, Traoré M, Zwick V, Berry L, Simões-Pires C, Cuendet M, Fantozzi N, Pereira de Freitas R, Maynadier M, Wein S, Vial H, Wong, YS.
Synthesis of an uncharged tetra-cyclopeptide acting as transmembrane carrier: enhanced cellular and nuclear uptake.
Organic Letters, 2017, 19(3):612-615.

Patent: Peyrottes S., Perigaud C., Wein S., Acyclonucléosides phosphonates, leurs prodrogues, et leur utilisation en tant que médicaments. N° 17 52405, Déposé par Université de Montpellier, CNRS et ENSC. Mars 2017.

Traoré M, Zwick V, Simões-Pires C, Nurisso A, Issa M, Cuendet M, Maynadier M., Wein S.; Vial HJ., Helene; Wong YS.
Hydroxyl Ketone-Based Histone Deacetylase Inhibitors To Gain Insight into Class I HDAC Selectivity versus That of HDAC6.
ACS Omega, 2017, 2 (4), pp 1550–1562

2016

Daher, W., Morlon-Guyot, J., Alayi, T.D., Tomavo, S., Wengelnik, K., Lebrun, M.
Identification of Toxoplasma TgPH1, a pleckstrin homology domain-containing protein that binds to the phosphoinositide PI(3,5)P2.
Mol. Biochem. Parasitol., 2016, 207, 39-44.

Guca, E., Contet, A., Vial, H.J., Wengelnik, K., Cerdan, R., 2016.
Phosphatidylcholine and Phosphatidylethanolamine Biosynthesis Pathways in Plasmodium,
Comprehensive Analysis of Parasite Biology: From Metabolism to Drug Discovery. Wiley-VCH Verlag GmbH & Co. KGaA, pp. 171-191. Review

2015

Contet, A., Pihan, E., Lavigne, M., Wengelnik, K., Maheshwari, S., Vial, H., Douguet, D., Cerdan, R.
Plasmodium falciparum CTP:phosphocholine cytidylyltransferase possesses two functional catalytic domains and is inhibited by a CDP-choline analog selected from a virtual screening.
FEBS Lett., 2015, 589, 992-1000.

Daher, W., Morlon-Guyot, J., Sheiner, L., Lentini, G., Berry, L., Tawk, L., Dubremetz, J.F., Wengelnik, K., Striepen, B., Lebrun, M.
Lipid kinases are essential for apicoplast homeostasis in Toxoplasma gondii.
Cell. Microbiol., 2015, 17, 559-578.

Winkler M, Maynadier M, Wein S, Lespinasse MA, Boumis G, Miele AE, Vial H, Wong YS.
Uncovering new structural insights for antimalarial activity from cost-effective aculeatin-like derivatives.
Org Biomol Chem., 2015 Feb 21;13(7):2064-77.

2014

Wein S, C. Tran Van Ba, M. Maynadier, Y. Bordat, J. Perez, S. Peyrottes, L. Fraisse, H. Vial.
New insight in the mechanism of accumulation and intraerythrocytic compartmentation of albitiazolium - a new type of antimalarial.
Antimicrob Agents Chemother, 2014, Sep;58(9):5519-27.

Degardin M, Wein S, Duckert JF, Maynadier M, Guy A, Durand T, Escale R, Vial H, Vo-Hoang Y.
Development of the first oral bioprecursors of bis-alkylguanidine antimalarial drugs.

ChemMedChem, 2014, Feb;9(2):300-4.

Peyrottes S, Caldarelli S, Wein S, Perigaud C, Vial H.
Exploring prodrug approaches for albitiazolium and its analogues. Exploring prodrug approaches for albitiazolium and its analogues.
Curr Top Med Chem, 2014; 14(14): 1653-67.

Nagy G.N., Marton L., Contet, A., Ozohanics, O., Ardelean, L.M., Révész A., Vékey, K., Irimie, F.D., Vial, H., Cerdan R., Vértessy B.G.
Composite aromatic boxes for enzymatic transformations of quaternary ammonium substrates.
Angew Chem Int. Ed Engl., 2014, 53, 13471-6.

Vial, H.J., Wengelnik, K., 2014.
Phospholipid metabolism, in: Hommel, M., Kremsner, P.G. (Eds.), Encyclopedia of Malaria. Springer. Review

2013

Maheshwari, S., Lavigne, M., Contet, A., Alberge, B., Pihan, E., Kocken, C., Wengelnik, K., Douguet, D., Vial, H., Cerdan, R.
Biochemical characterization of Plasmodium falciparum CTP:phosphoethanolamine cytidylyltransferase shows that only one of the two cytidylyltransferase domains is active.
Biochem. J., 2013, 450, 159-167.

Caldarelli SA, El Fangour S, Wein S, Tran van Ba C, Périgaud C, Pellet A, Vial HJ, Peyrottes S.
New bis-thiazolium analogues as potential antimalarial agents: design, synthesis, and biological evaluation.
J Med Chem., 2013 Jan, 56(2):496-509.

Lombard MC, N'da DD, Tran Van Ba C, Wein S, Norman J, Wiesner L, Vial H.
Potent in vivo anti-malarial activity and representative snapshot pharmacokinetic evaluation of artemisinin-quinoline hybrid.
Malar J., 2013 Feb,12:71

2012

Wein S, Maynadier M, Bordat Y, Perez J, Maheshwari S, Bette-Bobillo P, Tran Van Ba C, Penarete-Vargas D, Fraisse L, Cerdan R, Vial H.
Transport and pharmacodynamics of albitiazolium, an antimalarial drug candidate.
Br J Pharmacol., 2012 Aug, 166(8):2263-76.

Peyrottes S, Caldarelli S, Wein S, Périgaud C, Pellet A, Vial H.
Choline analogues in malaria chemotherapy. Curr Pharm Des. 2012,18(24):3454-66. Review.

Caldarelli SA, Hamel M, Duckert JF, Ouattara M, Calas M, Maynadier M, Wein S, Périgaud C, Pellet A, Vial HJ, Peyrottes S.
Disulfide prodrugs of albitiazolium (T3/SAR97276): synthesis and biological activities.
J Med Chem., 2012 May, 55(10):4619-28.

Lombard MC, N'Da DD, Breytenbach JC, Kolesnikova NI, Tran Van Ba C, Wein S, Norman J, Denti P, Vial H, Wiesner L.
Antimalarial and anticancer activities of artemisinin-quinoline hybrid-dimers and pharmacokinetic properties in mice.
Eur J Pharm Sci., 2012 Dec, 47(5):834-41.

Degardin M, Wein S, Gouni S, Tran Van Ba C, Duckert JF, Durand T, Escale R, Vial H, Vo-Hoang Y.
Evaluation of bis-alkylamidoxime O-alkylsulfonates as orally available antimalarials.
ChemMedChem., 2012 Jun, 7(6):991-1001

2011

Zaknoon F, Wein S, Krugliak M, Meir O, Rotem S, Ginsburg H, Vial H, Mor A .
Antiplasmodial properties of acyl-lysyl oligomers in culture and animal models of malaria.
Antimicrob Agents Chemother, 2011, 55(8): 3803-3811.

Vial H, Penarete D, Wein S, Caldarelli S, Fraisse L, Peyrottes S.
Lipids as drug targets for malaria therapy, In “Drug discovery in infectious diseases, volume 2. Apicomplexan parasites: Molecular approaches toward targeted drug development", K Becker Ed, Wiley Blackwell Press February 15th, 2011.

Margout D, Gattacceca F, Moarbess G, Wein S, Tran van Ba C, Le Pape S, Berger O, Escale R, Vial HJ, Bressolle FM.
Pharmacokinetic properties and metabolism of a new potent antimalarial N-alkylamidine compound, M64, and its corresponding bioprecursors.
Eur J Pharm Sci., 2011, 42(1-2):81-90.

Raabe, A., Berry, L., Sollelis, L., Cerdan, R., Tawk, L., Vial, H.J., Billker, O., Wengelnik, K.
Genetic and transcriptional analysis of phosphoinositide-specific phospholipase C in Plasmodium.
Exp. Parasitol., 2011, 129, 75-80.

Raabe, A.C., Wengelnik, K., Billker, O., Vial, H.J.
Multiple roles for Plasmodium berghei phosphoinositide-specific phospholipase C in regulating gametocyte activation and differentiation.
Cell. Microbiol., 2011, 13, 955-966.

Tawk, L., Dubremetz, J.F., Montcourrier, P., Chicanne, G., Merezegue, F., Richard, V., Payrastre, B., Meissner, M., Vial, H.J., Roy, C., Wengelnik, K., Lebrun, M.
Phosphatidylinositol 3-monophosphate is involved in Toxoplasma apicoplast biogenesis.
PLoS Pathog., 2011, 7, e1001286.

2010

Wein S, Maynadier M, Tran Van Ba C, Cerdan R, Peyrottes S, Fraisse L, Vial H.
Reliability of antimalarial sensitivity tests depends on drug mechanisms of action.
J Clin Microbiol., 2010, May;48(5):1651-60.

Tawk, L., Chicanne, G., Dubremetz, J.F., Richard, V., Payrastre, B., Vial, H.J., Roy, C., Wengelnik, K.
Phosphatidylinositol 3-phosphate, an essential lipid in Plasmodium, localizes to the food vacuole membrane and the apicoplast.
Eukaryot. Cell, 2010, 9, 1519-1530.

Berger O, Wein S, Duckert JF, Maynadier M, El Fangour S, Escale R, Durand T, Vial H, Vo-Hoang Y.
Reverse-benzamidine antimalarial agents: design, synthesis, and biological evaluation.
Bioorganic & Medicinal Chemistry Letters, 2010, 20, (19): 5815-5817.

Caldarelli S, Boisbrun M, Alarcon K, Hamzé A, Ouattara M, Salom-Roig X, Maynadier M, Wein S, Peyrottes S, Pellet A, Calas M. and Vial H.
Exploration of potential prodrug approach of the bis-thiazolium salts T3 and T4 for orally delivered antimalarials,
Bioorganic & Medicinal Chemistry Letters, 2010, 20, 3953-3956.

Caldarelli S, Duckert J.F, Wein S, Calas M, Périgaud C, Vial H and Peyrottes S.
Synthesis and Evaluation of Bis-Thiazolium Salts as Potential Antimalarial Drugs.
ChemMedChem, 2010, 5, 1–9.

Ortial S, Denoyelle S, Wein S, Berger O, Durand T, Escale R, Pellet A, Vial H, Vo-Hoang Y.
Synthesis and evaluation of hybrid bis-cationic salts as antimalarial drugs.
ChemMedChem, 2010 Jan;5(1):52-5.

Dechamps, S., Shastri, S., Wengelnik, K., Vial, H.J.
Glycerophospholipid acquisition in Plasmodium - a puzzling assembly of biosynthetic pathways.
Int. J. Parasitol., 2010, 40, 1347-1365. Review

Dechamps, S., Wengelnik, K., Berry-Sterkers, L., Cerdan, R., Vial, H.J., Gannoun-Zaki, L.
The Kennedy phospholipid biosynthesis pathways are refractory to genetic disruption in Plasmodium berghei and therefore appear essential in blood stages. Mol. Biochem. Parasitol., 2010, 173, 69-80.

Déchamps S, Maynadier M, Wein S, Gannoun-Zaki L, Maréchal E, Vial HJ.
Rodent and nonrodent malaria parasites differ in their phospholipid metabolic pathways.
J Lipid Res., 2010 Jan;51(1):81-96

2009

Degardin M, Wein S, Durand T, Escale R, Vial H, Vo-Hoang Y.
N-substituted bis-C-alkyloxadiazolones as dual effectors: efficient intermediates to amidoximes or amidines and prodrug candidates of potent antimalarials.
Bioorg Med Chem Lett., 2009 Sep 1;19(17):5233-6.

Margout D, Wein S, Gandon H, Gattacceca F, Vial HJ, Bressolle FM.
Quantitation of SAR97276 in mouse tissues by rapid resolution liquid chromatography-mass spectrometry.
J Sep Sci., 2009 Jun;32(11):1808-15.

Ouattara M, Wein S, Denoyelle S, Ortial S, Durand T, Escale R, Vial H, Vo-Hoang Y.
Design and synthesis of amidoxime derivatives for orally potent C-alkylamidine-based antimalarial agents.
Bioorg Med Chem Lett., 2009 Feb 1;19(3):624-6.

Kocken CH, Remarque EJ, Dubbeld MA, Wein S, van der Wel A, Verburgh RJ, Vial HJ, Thomas AW.
Statistical model to evaluate in vivo activities of antimalarial drugs in a Plasmodium cynomolgi-macaque model for Plasmodium vivax
malaria. Antimicrob Agents Chemother., 2009 Feb;53(2):421-7.

Raabe, A.C., Billker, O., Vial, H.J., Wengelnik, K.
Quantitative assessment of DNA replication to monitor microgametogenesis in Plasmodium berghei.
Mol. Biochem. Parasitol., 2009, 168, 172-176.

selected articles before 2009

Patent: Vial HJ, Wein S. & Fraisse L, Association entre un sel de bis-thiazolium et l’artémisinine pour le traitement du paludisme. EU 07290683.7, Déposé par Sanofi et CNRS Février 2008.

Vial HJ, Wein S, Farenc C, Kocken C, Nicolas O, Ancelin ML, Bressolle F, Thomas A, Calas M.
Prodrugs of bisthiazolium salts are orally potent antimalarials.
Proc Natl Acad Sci U S A., 2004 Oct 26;101(43):15458-63.

Wengelnik, K., Vidal, V., Ancelin, M.L., Cathiard, A.M., Morgat, J.L., Kocken, C.H., Calas, M., Herrera, S., Thomas, A.W., Vial, H.J.
A class of potent antimalarials and their specific accumulation in infected erythrocytes.
Science, 2002, 295, 1311-1314.