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Redox metabolism in tropical malaria

Redox metabolism in tropical malaria - an approach to rational drug design

(Project A12 SFB 535 and Be 2554/1-2)

 

Tropical malaria, caused by an infection of erythrocytes with the protozoan parasite Plasmodium falciparum, threatens almost half of the world's population. Almost a million people die from malaria each year - most of them are children under the age of five. Cerebral malaria, which is particularly dangerous, is characterized by hallucinations and unconsciousness up to coma and death. Parasite resistance against the antimalarial drugs currently in use as well as the geographical distribution of the disease are increasing. Therefore new prophylactic and therapeutic strategies are urgently required.

Reactive oxygen species (ROS) and nitrogen species (NOS) are continuously generated in metabolically active tissues. During infections this production is increased. Plasmodium falciparum is particularly susceptible to oxidative and nitrosative stress. This is likely to explain the partial resistance of glucose-6-phosphate dehydrogenase (G6PDH)-deficient individuals against malaria. However, apart from the toxic effects of oxidative stress, reactive oxygen and nitrogen species are essentially involved in regulation of cellular growth and differentiation.

The enzymes thioredoxin reductase (TrxR) and glutathione reductase (GR) as well as their substrates thioredoxin and glutathione represent cornerstones of the cellular defense against oxidative stress. They are furthermore involved in deoxyribonucleotide production, in redox control of different metabolic pathways, and in cell proliferation and differentiation. Therefore not only GRs and TrxRs but also other antioxidant enzymes represent promising target molecules for rational drug design against malaria.

 

By studying the redox metabolism of cells parasitized with malaria, we hope to:

 

  1.  learn more about parasite biology
  2.  understand parasite-host cell interactions
  3.  contribute to the development of new antimalarial drugs

   

The following methods are used:

  

  • Cloning and overexpression of genes coding for redox-active proteins from man, the malaria parasite Plasmodium falciparum, and the malaria-transmitting mosquito Anopheles gambiae
  • Comparative structural and functional characterization of the proteins and their substrates (enzyme kinetics, crystallization, localization, stage-specific expression)
  • Drug screening on malaria parasites and on isolated enzymes; rational drug design
  • Cultivation of P. falciparum, characterization of the redox reactions in various parasite strains