title: An assessment of drug-haematin binding as a mechanism for inhibition of haematin polymerisation by quinoline antimalarials.
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.
authors.affiliation: Pharma Division, Preclinical Research, F. Hoffmann-La Roche Ltd, Basel, Switzerland.
authors.forename: A
authors.initials: A
authors.lastname: Dorn
authors.forename: S R
authors.initials: SR
authors.lastname: Vippagunta
authors.forename: H
authors.initials: H
authors.lastname: Matile
authors.forename: C
authors.initials: C
authors.lastname: Jaquet
authors.forename: J L
authors.initials: JL
authors.lastname: Vennerstrom
authors.forename: R G
authors.initials: RG
authors.lastname: Ridley
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000378:metabolism*; D001704:Biopolymers; D019277:Entropy; D005069:Evaluation Studies as Topic; D006427:Hemin / Q000378:metabolism*; D006863:Hydrogen-Ion Concentration; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000254:growth & development; D011804:Quinolines / Q000378:metabolism*; D013816:Thermodynamics
chemical_list: D000962:Antimalarials; D001704:Biopolymers; D011804:Quinolines; D006427:Hemin