Chloroquine food vacuole

Chloroquine (Aralen) is one of several 4-aminoquino-line derivatives that display antimalarial activity. Chloroquine is particularly effective against intraerythrocytic forms because it is concentrated within the parasitized erythrocyte. This preferential drug accumulation appears to occur as a result of specific uptake mechanisms in the parasite. Chloroquine appears to work by intercalation with DNA, inhibition of heme polymerase or by interaction with Ca++-calmodulin-mediated mechanisms. It also accumulates in the parasite s food vacuoles, where it inhibits peptide formation and phospholipases, leading to parasite death. 

Chloroquine probably acts by concentrating in parasite food vacuoles, preventing the biocrystallization of the hemoglobin breakdown product, heme, into hemozoin, and thus eliciting parasite toxicity due to the buildup of free heme. 

Thus a combination of chloroquine with the agents that cured P. falciparum of its apicoplast may be helpful in preventing the parasite from invading new host cells, and this combination may also kill the parasite, because it could not then flux out accumulated chloroquine in its digestive food vacuole. 

How the parasite removes chloroquine from the food vacuole appears to be related to mutations of a specific gene, named pfcrt for plasmodium falciparum chloroquine resistance transporter. The protein product of this gene (CRT) is a 49 kD transmembrane protein that has a predicted 10 transmembrane domains. The key mutation seems to be K76T since no chloroquine resistant isolate carries the wild type lysine at position 76. It should be noted that usually a number of other mutations are noted in chloroquine resistant malaria, but only the K76T amino acid switch is seen consistently in the chloroquine resistant malaria. 

The membrane of the food vacuole has other transporter proteins associated with it. One such protein, encoded by the pfmdrl gene, shows structural similarity to the human PGP that was discussed earlier in this chapter. This malaria protein has a molecular weight of 162 kD, and is an ABC transporter with 12 transmembrane domains and two ATP binding folds. The mammalian PGP pumps drug out of the cell but the malarial MDRl actually pumps drugs into the food vacuole. Although this protein can add to the resistance associated with K76T mutation of the CRT protein, by itself it does not provide a chloroquine resistant... 

In order to study the distribution of ferroquine, ruthenoquine 56, an analog of ferroquine was prepared, in which the iron is replaced by ruthenium, a well-known contrasting agent in electron microscopy (Scheme 3.22) [139], Chemically, ruthenoquine is similar to ferroquine and possesses similar antimalarial activity. In infected mice treated with ruthenoquine, Ru atoms have been detected in the food vacuole, not only close to the malarial pigment but also in the membrane of the parasite. This clear difference from the case of chloroquine, which is never found in the membrane, could account for the difference in activity. 

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