Chloroquine - some open questions on its antimalarial mode of action and resistance

During the digestion of its host cell hemoglobin, large amounts of toxic ferriprotoporphyrin IX (FPIX) are generated in the intraerythrocytic malaria parasite. FPIX is detoxified either by being polymerized into hemozoin inside the food vacuole, or through its degradation by glutathione in the cytosol. Chloroquine is able to complex with FPIX, thus inhibiting both processes and thereby generating receptors for its own uptake. These leads to the accumulation of FPIX in the membrane fraction of infected cells that results in membrane permeabilization and disruption of cation homeostasis and concluded in parasite death. Several unresolved questions, such as the site of FPIX:chloroquine complex formation, the role of pH gradient in drug accumulation and resistance, the role of Pgh-1 in resistance, the mode of action of reversers and the involvement of proteins and their mutants in resistance, are discussed.