Reaction of antimalarial endoperoxides with specific parasite proteins.
The endoperoxides are a new class of antimalarial agents, of which artemisinin (qinghaosu) is the prototype. We have previously shown that artemisinin is capable of alkylating proteins in model reactions. In the present study, we showed that when Plasmodium falciparum-infected erythrocytes are treated with a radiolabeled antimalarial endoperoxide, either arteether, dihydroartemisinin, or Ro 42-1611 (arteflene), the radioactivity is largely coverted into a form which can be extracted with sodium dodecyl sulfate (SDS). Autoradiograms of SDS-polyacrylamide gels showed that six malarial proteins are radioactively labeled by the three endoperoxides. This labeling occurs at physiological concentrations of drug and is not stage nor strain specific. The labeled proteins were not the most abundant proteins seen on Coomassie-stained gels. No proteins were labeled when uninfected erythrocytes were treated with these drugs, nor when infected erythrocytes were treated with the inactive analog deoxyarteether. Thus, the antimalarial endoperoxides appear to react with specific malarial proteins.
Asawamahasakda
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W
Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor 48109.
Ittarat
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Pu
Y M
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Ziffer
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Meshnick
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D000818:Animals; D000962:Antimalarials / Q000378:metabolism*; D037621:Artemisinins; D001345:Autoradiography; D001643:Bridged Bicyclo Compounds / Q000378:metabolism*; D019086:Bridged Bicyclo Compounds, Heterocyclic; D004912:Erythrocytes / Q000469:parasitology; D010963:Plasmodium falciparum / Q000378:metabolism*; D015800:Protozoan Proteins / Q000378:metabolism*; D012717:Sesquiterpenes / Q000378:metabolism*; D013343:Styrenes / Q000378:metabolism*
D000962:Antimalarials; D037621:Artemisinins; D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D015800:Protozoan Proteins; D012717:Sesquiterpenes; D013343:Styrenes; C090720:arteflene; C039060:artenimol; C055141:artemotil