Title:Plasmodium Drug Targets Outside the Genetic Control of the Parasite
Volume: 19
Issue: 2
Author(s): David J. Sullivan
Affiliation:
Keywords:
Heme, drug, iron, malaria, host defense peptide
Abstract: Drug development often seeks to find “magic bullets” which target microbiologic proteins while not affecting host proteins.
Paul Ehrlich tested methylene blue as an antimalarial but this dye was not superior to quinine. Many successful antimalarial therapies are
“magic shotguns” which target many Plasmodium pathways with little interference in host metabolism. Two malaria drug classes, the 8-
aminoquinolines and the artemisinins interact with cytochrome P450s and host iron protoporphyrin IX or iron, respectively, to generate
toxic metabolites and/or radicals, which kill the parasite by interference with many proteins. The non 8-amino antimalarial quinolines like
quinine or piperaquine bind heme to inhibit the process of heme crystallization, which results in multiple enzyme inhibition and membrane
dysfunction. The quinolines and artemisinins are rapidly parasiticidal in contrast to metal chelators, which have a slower parasite
clearance rate with higher drug concentrations. Iron chelators interfere with the artemisinins but otherwise represent a strategy of targeting
multiple enzymes containing iron. Interest has been revived in antineoplastic drugs that target DNA metabolism as antimalarials.
Specific drug targeting or investigation of the innate immunity directed to the more permeable trophozoite or schizont infected erythrocyte
membrane has been under explored. Novel drug classes in the antimalarial development pipeline which either target multiple proteins
or unchangeable cellular targets will slow the pace of drug resistance acquisition.