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Query: UMLS:C0024530 (malaria)
 44,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

New strategies targeting Plasmodium falciparum gametocytes, the sexual-stage parasites that are responsible for malaria transmission, are needed to eradicate this disease. Most commonly used antimalarials are ineffective against P. falciparum gametocytes, allowing patients to continue to be infectious for over a week after asexual parasite clearance. A recent screen for gametocytocidal compounds demonstrated that the carboxylic polyether ionophore maduramicin is active at low nanomolar concentrations against P. falciparum sexual stages. In this study, we showed that maduramicin has an EC50 (effective concentration that inhibits the signal by 50%) of 14.8 nM against late-stage gametocytes and significantly blocks in vivo transmission in a mouse model of malaria transmission. In contrast to other reported gametocytocidal agents, maduramicin acts rapidly in vitro, eliminating gametocytes and asexual schizonts in less than 12 h without affecting uninfected red blood cells (RBCs). Ring stage parasites are cleared by 24 h. Within an hour of drug treatment, 40% of the normally crescent-shaped gametocytes round up and become spherical. The number of round gametocytes increases to >60% by 2 h, even before a change in membrane potential as monitored by MitoProbe DiIC1 (5) is detectable. Maduramicin is not preferentially taken up by gametocyte-infected RBCs compared to uninfected RBCs, suggesting that gametocytes are more sensitive to alterations in cation concentration than RBCs. Moreover, the addition of 15.6 nM maduramicin enhanced the gametocytocidal activity of the pyrazoleamide PA21A050, which is a promising new antimalarial candidate associated with an increase in intracellular Na(+) concentration that is proposed to be due to inhibition of PfATP4, a putative Na(+) pump. These results underscore the importance of cation homeostasis in sexual as well as asexual intraerythrocytic-stage P. falciparum parasites and the potential of targeting this pathway for drug development.
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PMID:Maduramicin Rapidly Eliminates Malaria Parasites and Potentiates the Gametocytocidal Activity of the Pyrazoleamide PA21A050. 2671 68

Malaria continues to be one of the deadliest infectious diseases and a global health menace. The emergence and spread of drug-resistant strains of malaria parasites have further made the process of disease management grimmer. Thus, there is an urgent need to identify promising antimalarial strategies that can target the blood stages as well as block parasite transmission. Maduramicin is one such ionophore selected out of a recent screen of gametocytocidal compounds that exhibit potent antiplasmodial activity. However, maduramicin's strong hydrophobic nature and associated toxicity restrict its application in chemotherapy. To alleviate this problem, we have developed a liposomal formulation loaded with the ionophore maduramicin for the treatment of chloroquine sensitive and resistant Plasmodium infections. Here, we show that maduramicin in PEGylated liposomal formulations displayed enhanced antiplasmodial activity in vitro compared to free maduramicin. Significantly, four consecutive doses of 1.5 mg kg-1 body weight of PEGylated maduramicin loaded lipid vesicles completely cured cerebral and chloroquine resistant murine models of malaria without any obvious toxic effects and suppressed the key inflammatory markers associated with the progression of the disease. PEGylated liposomal maduramicin also exhibited a prolonged plasma clearance rate, implying a greater chance of interaction and uptake by infected RBCs. Furthermore, we also provide evidence that the detrimental effect of liposomal maduramicin on parasite survival is mediated by increased ROS generation and subsequent perturbation of parasite mitochondrial membrane potential. This study presents the first report to demonstrate the potent antimalarial efficacy of maduramicin liposomes, a strategy that holds promise for the development of successful therapeutic intervention against malaria in humans.
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PMID:Long circulatory liposomal maduramicin inhibits the growth of Plasmodium falciparum blood stages in culture and cures murine models of experimental malaria. 2999 25

Plasmodium has a complex life cycle that spans between mosquito and human. For survival and pathogenesis it banks upon dynamic alterations in ionic transport across organelle and plasma membrane. Being a fundamental contributor of crucial biological processes in parasite, ionic balance facilitates parasite invasion, augmentation and transmission. Past few decades have witnessed tremendous advancement in understanding the relevance of ionic transit in parasites. Perhaps, not surprisingly, disruption of ionic homeostasis was thought to be detrimental for parasite. Compounds like ionophores are known to facilitate ionic transport across membrane down their electrochemical gradient. Despite continuous effort, malaria treatment is still a challenge particularly due to the development of resistance among parasites against existing therapeutic options. However, repurposing the existing drugs can be advantageous over de novo drug development programs in terms of cost and associated risk factors. Ionophores, being used in coccidiosis have proven to be of significance in the treatment of experimental models of malaria. Several recent reports have highlighted the attractive potential of ionophores such as Monensin, Maduramicin, Valinomycin, etc., that can act against multiple stages of malarial parasite's life cycle. Improved variety of these molecules may help in mitigating the drug resistance problems as well. This review is an attempt to examine the relevant literature and provide insight into the mechanism and prospects of different classes of ionophores as promising anti-malarial potpourri.
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PMID:Ionophores as Potent Anti-malarials: A Miracle in the Making. 3049 90