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Chloroquine 4-aminoquilonine basic Works by inhibiting the polymerization of haem to haemozoin by a biophysical process and not by inhibiting enzymes

as first thought. It accumulates in the acidic food vacuole which is where haemoglobin is broken down by basic action. The subsequent accumulation of the haem is toxic to the parasite and kills it. Chloroquine resistance can either arise by reducing influx of chloroquine into the food vacuole or increasing efflux of chloroquine out of the food vacuole or inhibiting the action of chloroquine in some way in the food vacuole. Current evidence seems to favour the is thought to arise by the prevention of accumulation of chloroquine in the food vacuole by a mutated version of a protein called plasmodium falciparum Chloroquine Resistance Transporter (pfCRT) which is encoded by a gene called pfcrt on chromosome 7 of the parasite. Chloroquine is transported into the food vacuole of the parasite by diprotonated from (CQ2+) in the

The exact function of pfCRT is not known but is known to be a member of the membrane drug transporter (mdt) family. It is implicated in the transport of peptides etc??? Characteristics of chloroquine resistance including a reversion to chloroquine susceptibility when vaerapamil, a well known calcium channel blocker used in chemotherapy of mammalian cancerous cells, is applied. Other characteristics include an increased IC50 (about 100nM in vitro), reduced pH in the food vacuole, reduced accumulation of chloroquine in the food vacuole and characteristic mutations in pfcrt. pfCRT 10 domains, diagram with key mutations Substitution of lysine (K) by threonine (T) at codon 76 is a mutation that has been found in almost all studies of chloroquine resistance and is denoted by K76T. A laboratory study reported a mutation of K76I which conferred the same chloroquine resistance phenotype. The two mutations replace a neutral amino-acid with a positively charged one and it is thought that this prevents the influx of chloroquine into the food vacuole due to electrical repulsion??? The action of verapamil in reversing resistance is thought to arise by providing an alternative, neutral path for the influx of chloroquine.

K76T is thus thought to be the key mutation necessary for chloroquine resistance. However, other mutations on pfCRT are always observed together with the K76T mutation suggesting that the resistance conferred by K76T comes at a survival/fitness cost. Some of these mutations are A220S etc and are thought to compensate for the fitness loss. The increased pH in the food vacuole which is contrary to what was initially expected and measured is thought to reduce the binding of chloroquine to haem hence less efficient inhibition of polymerization. (WHY supprised? Increased pH means lower base which means less chloroquine accumulation.. depends on model of resistance thought at the time??) Role of mutations in other genes which seem to reinforce the chloroquine resistance notably pfmdr1 which codes for Pgh-1 (plasmodium glycoprotein 1??) Cross resistance- CQR more susceptible to other drugs, also resistant to other quinines (4- & 8- aminoquinolines?? how much??) Fitness cost of CQR observed in Malawi- after cessation of chloroquine use, pfCRT mutations reduced. Not so in SE Asia where despite cessation of chloroquien use, pfCRT mutations still high proportion of parasites. Foci of resistance Originally developed in SE Asia in early 60s, then spread to Africa in 70s, South America involved as well? Over run Africa, only Caribbean islands free of CQR.