Novel Leishmania and Malaria Potassium Channels: Candidate Therapeutic Targets
Final rept. 18 Mar 2002-17 Jul 2005
ALBERT EINSTEIN COLL OF MEDICINE OF (YESHIVA UNIV) BRONX NY
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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.
- *PLASMODIUM FALCIPARUM
- ARTHROPOD BORNE DISEASES
- IMMUNE SERUMS