An assessment of drug-haematin binding as a mechanism for inhibition of haematin polymerisation by quinoline antimalarials.

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Dorn A, Vippagunta SR, Matile H, Jaquet C, Vennerstrom JL, Ridley RG

An assessment of drug-haematin binding as a mechanism for inhibition of haematin polymerisation by quinoline antimalarials.

Biochem Pharmacol. 1998 Mar 15;55(6):727-36.

PubMed ID

9586944 [ View in PubMed

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Abstract

Chloroquine is thought to exert its antimalarial activity by preventing the polymerisation of toxic haematin released during proteolysis of haemoglobin in the Plasmodium digestive vacuole. However, the molecular mechanisms by which this inhibition occurs and the universality of this mechanism for other quinoline antimalarials remain to be established. We demonstrate here a correlation for eight antimalarial quinolines between inhibition of haematin polymerisation in vitro and inhibition of P. falciparum growth in culture, confirming haematin polymerisation as the likely target of quinoline blood schizonticides. Furthermore, using isothermal titration microcalorimetry, a correlation was observed between the haematin binding constant of these compounds and their ability to inhibit haematin polymerisation, suggesting that these compounds mediate their activity through binding to haematin. It was also observed that the compounds bind primarily to the mu-oxo dimer form of haematin rather than the monomeric form. It is postulated that this binding inhibits haematin polymerisation by shifting the haematin dimerisation equilibrium to the mu-oxo dimer, thus reducing the availability of monomeric haematin for incorporation into haemozoin. These data reconcile the haematin polymerisation theory with the Fitch hypothesis, which states that chloroquine mediates its activity through binding to haematin.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Primaquine	Fe(II)-protoporphyrin IX	Small molecule	Plasmodium falciparum	Yes	Antagonist	Details