Beating the malaria parasite at its own game

Abstract

Currently 40% of the world's population is still at risk of becoming infected with malaria, which is an even more worrisome disease because of drug resistance and multidrug resistance. Research on drug resistance is suggesting new ways to attack the parasite by designing selectively toxic compounds. At Washington University, a study has been centering on how malarial parasites developed resistance to antimalarial drugs. A new class of compounds have been developed that block haem polymerization to haemazoin and kill the parasite. These hexadentate metal complexes that bypass the current resistance mechanisms are made from aspirin and are being tested in animals. A new resistance gene also been identified that transports chloroquine out of the parasite or blocks the drug's influx, leaving the parasite unharmed. In addition, a gene associated with mefloquine resistance was isolated at Harvard University. A large number drug transporter inhibitors have also been identified, but none is sufficiently selective for the parasite's transporter. In Oxford, UK, recently, the low-resolution structure of the human multidrug resistant P-glycoprotein was also solved, which might permit the design of modified antimalarial drugs. Exploiting the differences between parasite and human enzymes may also provide new drug targets. The crystal structure of a complex between plasmepsin, a parasite aspartate protease that initiates the digestion of hemoglobin, and an inhibitor has also been revealed. The crystal structure of lactate dehydrogenase (LDH) from Plasmodium falciparum has also been determined finding a big difference around the active site of the malarial enzyme and mammalian LDH. Parasite enzymes are being researched by other scientists elsewhere. At the University of Montpellier, France, the work on the parasite's choline carrier is more advanced. One of three compounds that kill parasites will be chosen for clinical studies.