Antimalarial properties of bredinin. Prediction based on identification of differences in human host-parasite purine metabolism.
Human malaria parasites (Plasmodium falciparum) grown in continuous erythrocyte culture utilize hypoxanthine for synthesis of both guanosine and adenosine nucleotides. Unlike the mature human erythrocyte, the malaria parasite depends on a constant supply of guanylates, primarily for synthesis of nucleic acids. This parasite specific requirement for guanylates led us to predict that a block in the hypoxanthine to guanosine monophosphate pathway would be selectively lethal to the parasite. Bredinin (4-carbamoyl-1-beta-D-ribofuranyosyl-imidazolium-5-olate) inhibited the synthesis of guanosine monophosphate from inosine monophosphate by parasitized erythrocytes. This block in guanylate synthesis was fatal to both a drug-sensitive (FCR-3) and a drug-resistant (VNS) strain of the malaria parasite at a bredinin concentration of 50 microM, arresting growth of the parasite at the trophozoite stage of development. These studies emphasize the essential role of guanylates and their synthesis from hypoxanthine in the metabolism of malaria parasite. They further suggest that bredinin or similar agents that selectively interfere with parasite guanylate metabolism may have potential for antimalarial chemotherapy.
D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D004912:Erythrocytes / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D019271:Hypoxanthine; D007042:Hypoxanthines / Q000378:metabolism; D010963:Plasmodium falciparum / Q000187:drug effects / Q000378:metabolism*; D011687:Purines / Q000378:metabolism*; D012263:Ribonucleosides / Q000494:pharmacology*
D007042:Hypoxanthines; D011687:Purines; D012263:Ribonucleosides; D019271:Hypoxanthine; C010052:mizoribine; C030985:purine