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Pathway Description
Halofantrine Action Pathway
Homo sapiens
Drug Action Pathway
Halofantrine is an synthetic antimalarial used for the treatment of severe malaria. It is effective against multi drug resistant (including mefloquine resistant) P. falciparum malaria.
The mechanism of action of Halofantrine may be similar to that of chloroquine, quinine, and mefloquine; by forming toxic complexes with ferritoporphyrin IX that damage the membrane of the parasite. The plasmodium falciparum invades the erythrocytes in blood. Halofantrine accumulates in the parasite’s food vacuole and inhibits the enzyme heme ligase. Heme ligase is involved in hemoglobin breakdown. Hemoglobin from the erythrocyte is broken down in the digestive vacuole of the parasite. Hemoglobin is first broken down into heme and globin. Globin is further broken down to amino acids which are used by the parasite for nutrition and protein synthesis. Therefore, hemoglobin breakdown is essential for the parasite survival. The heme from hemoglobin is toxic to the parasite and is further broken down by heme ligase to detoxify heme. By halofantrine inhibiting heme ligase, there is a build up of heme in the parasite vacuole which becomes toxic to the parasite, thereby killing it.
References
Halofantrine Pathway References
Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. doi: 10.1038/nrd2199.
Pubmed: 17139284
Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. doi: 10.1038/nrd2132.
Pubmed: 17016423
Blauer G: Interaction of ferriprotoporphyrin IX with the antimalarials amodiaquine and halofantrine. Biochem Int. 1988 Oct;17(4):729-34.
Pubmed: 3240320
Egan TJ, Hempelmann E, Mavuso WW: Characterisation of synthetic beta-haematin and effects of the antimalarial drugs quinidine, halofantrine, desbutylhalofantrine and mefloquine on its formation. J Inorg Biochem. 1999 Jan-Feb;73(1-2):101-7. doi: 10.1016/S0162-0134(98)10095-8.
Pubmed: 10212997
Famin O, Krugliak M, Ginsburg H: Kinetics of inhibition of glutathione-mediated degradation of ferriprotoporphyrin IX by antimalarial drugs. Biochem Pharmacol. 1999 Jul 1;58(1):59-68. doi: 10.1016/s0006-2952(99)00059-3.
Pubmed: 10403519
de Villiers KA, Marques HM, Egan TJ: The crystal structure of halofantrine-ferriprotoporphyrin IX and the mechanism of action of arylmethanol antimalarials. J Inorg Biochem. 2008 Aug;102(8):1660-7. doi: 10.1016/j.jinorgbio.2008.04.001. Epub 2008 Apr 20.
Pubmed: 18508124
Fitch CD: Ferriprotoporphyrin IX, phospholipids, and the antimalarial actions of quinoline drugs. Life Sci. 2004 Mar 5;74(16):1957-72. doi: 10.1016/j.lfs.2003.10.003.
Pubmed: 14967191
Wishart DS, Feunang YD, Guo AC, Lo EJ, Marcu A, Grant JR, Sajed T, Johnson D, Li C, Sayeeda Z, Assempour N, Iynkkaran I, Liu Y, Maciejewski A, Gale N, Wilson A, Chin L, Cummings R, Le D, Pon A, Knox C, Wilson M: DrugBank 5.0: a major update to the DrugBank database for 2018. Nucleic Acids Res. 2018 Jan 4;46(D1):D1074-D1082. doi: 10.1093/nar/gkx1037.
Pubmed: 29126136
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