Towards a proteomic definition of CoArtem action in Plasmodium falciparum malaria

We have adopted a proteomic strategy to investigate the actions of the two active components of the new antimalarial CoArtem, artemether and lumefantrine, following pharmacologically relevant drug exposure in the human malaria parasite Plasmodium falciparum. Both drugs induced profound alterations in the parasite's proteome. Moreover, the pattern of proteome alteration was specific for the drug used. The two drugs induced opposing effects on key glycolytic enzymes while exerting similar influence of the expression of stress response proteins. These initial results demonstrate the power of this approach in the study of pleiomorphic mechanisms of drug action.

[1]  J. Hyde,et al.  Translational up-regulation of antifolate drug targets in the human malaria parasite Plasmodium falciparum upon challenge with inhibitors. , 2004, Molecular and biochemical parasitology.

[2]  N. White,et al.  Clinical Pharmacokinetics and Pharmacodynamics of Artemether-Lumefantrine , 1999 .

[3]  S. Meshnick,et al.  The Plasmodium falciparum translationally controlled tumor protein: subcellular localization and calcium binding. , 1999, European journal of cell biology.

[4]  P. Courchesne,et al.  Identification of proteins by matrix-assisted laser desorption/ionization mass spectrometry using peptide and fragment ion masses. , 1999, Methods in molecular biology.

[5]  J. Haynes,et al.  Quantitative assessment of antimalarial activity in vitro by a semiautomated microdilution technique , 1979, Antimicrobial Agents and Chemotherapy.

[6]  W. Trager,et al.  Human malaria parasites in continuous culture. , 1976, Science.

[7]  U. K. Laemmli,et al.  Cleavage of Structural Proteins during the Assembly of the Head of Bacteriophage T4 , 1970, Nature.

[8]  S. Krishna,et al.  Artemisinins target the SERCA of Plasmodium falciparum , 2003, Nature.

[9]  L. Gerena,et al.  Mechanism-based design, synthesis, and in vitro antimalarial testing of new 4-methylated trioxanes structurally related to artemisinin: the importance of a carbon-centered radical for antimalarial activity. , 1994, Journal of medicinal chemistry.

[10]  John E Hyde,et al.  Quantitative proteomics of the human malaria parasite Plasmodium falciparum and its application to studies of development and inhibition , 2004, Molecular microbiology.

[11]  J. Yates,et al.  Exploring the proteome of Plasmodium. , 2002, International journal for parasitology.

[12]  D. Carucci,et al.  Proteomic approaches to studying drug targets and resistance in Plasmodium. , 2004, Current drug targets. Infectious disorders.

[13]  S. Kyes,et al.  A simple RNA analysis method shows var and rif multigene family expression patterns in Plasmodium falciparum. , 2000, Molecular and biochemical parasitology.

[14]  A. Nzila,et al.  Antimalarial chemotherapy: young guns or back to the future? , 2003, Trends in parasitology.

[15]  David L. Tabb,et al.  A proteomic view of the Plasmodium falciparum life cycle , 2002, Nature.

[16]  J. Yates,et al.  A method for the comprehensive proteomic analysis of membrane proteins , 2003, Nature Biotechnology.

[17]  S. Meshnick,et al.  Artemisinin: mechanisms of action, resistance and toxicity. , 2002, International journal for parasitology.

[18]  P. Tarroux,et al.  Improvement and simplification of low‐background silver staining of proteins by using sodium dithionite , 1988, Electrophoresis.

[19]  Neil Hall,et al.  Analysis of the Plasmodium falciparum proteome by high-accuracy mass spectrometry , 2002, Nature.

[20]  D. L. Klayman,et al.  Qinghaosu (artemisinin): an antimalarial drug from China , 1985 .

[21]  D. Hochstrasser,et al.  Extraction of membrane proteins by differential solubilization for separation using two‐dimensional gel electrophoresis , 1998, Electrophoresis.

[22]  J. Dame,et al.  The Plasmodium falciparum Translationally Controlled Tumor Protein Homolog and Its Reaction with the Antimalarial Drug Artemisinin* , 1998, The Journal of Biological Chemistry.

[23]  A. Haase,et al.  MOLECULAR PATHOGENESIS OF HEPATITIS B VIRUS INFECTION: SIMULTANEOUS DETECTION OF VIRAL DNA AND ANTIGENS IN PARAFFIN-EMBEDDED LIVER SECTIONS , 1984, The Lancet.

[24]  Herbert Wj.  Multiple emulsions. A new form of mineral-oil antigen adjuvant. , 1965, Lancet.

[25]  Jonathan E. Allen,et al.  Genome sequence of the human malaria parasite Plasmodium falciparum , 2002, Nature.

[26]  S. Meshnick,et al.  Morphologic effects of artemisinin in Plasmodium falciparum. , 1993, The American journal of tropical medicine and hygiene.

[27]  Chun-Ming Huang,et al.  Proteomics reveals protein profile changes in doxorubicin--treated MCF-7 human breast cancer cells. , 2002, Cancer letters.

[28]  D. Warhurst,et al.  Uptake of [3H] dihydroartemisinine by erythrocytes infected with Plasmodium falciparum in vitro. , 1984, Transactions of the Royal Society of Tropical Medicine and Hygiene.

[29]  V. Neuhoff,et al.  Improved staining of proteins in polyacrylamide gels including isoelectric focusing gels with clear background at nanogram sensitivity using Coomassie Brilliant Blue G‐250 and R‐250 , 1988, Electrophoresis.

[30]  A. Bodley,et al.  Further evidence supporting the importance of and the restrictions on a carbon-centered radical for high antimalarial activity of 1,2,4-trioxanes like artemisinin. , 1995, Journal of medicinal chemistry.

[31]  Jason P Wendler,et al.  Mass spectrometric analysis of Plasmodium falciparum erythrocyte membrane protein‐1 variants expressed by placental malaria parasites , 2004, Proteomics.