Novel Leishmania and Malaria Potassium Channels: Candidate Therapeutic Targets

摘要

Chemotherapy against Arthropod-transmitted parasitic diseases is increasingly limited by the emergence of drug resistance. Development of new drugs has been slow, emphasizing the need for better, rational anti-parasitic drug discovery. Here we report our discovery of two new potassium ion (K+) channel genes in the genome databases of Plasmodium falciparum. MAJOR FINDINGS: To date, we have cloned genes encoding 10 potential K+ channel genes (2-each for F. falciparum, T. gondii, and 3 each for L. major and T. cruzi). Using a combination of cultured mammalian cells and Xenopus oocytes for heterologous expression we have evidence that 2 channels from malaria PFK1 & PFK22) and Leishmania LMK1 & LMK2) generate K+-selective conductances that are sensitive to block by antimalaria drugs chloroquine, quinidine and the K- channel blocker trifluoroperazine. Antisera against PFKI and PFK2 recognize appropriately sized proteins from P. Falciparum. Immunofluorescence of malaria- infected erythrocytes shows that PFK1 islocalized the host cell membrane while PFK2 is primarily associated with the parasite. We also showed that a series of K-channel blockers was capable of killing cultured malaria. Our results provide the first report of a cloned ion channel from an intracellular human parasite. Moreover, electrophysiology confirms their identity as K+ channels and pharmacology supports their potential as targets for drug therapy.