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

Arnulf Dorn, Sudha Rani Vippagunta, Hugues Matile, Catherine Jaquet, Jonathan L. Vennerstrom, Robert G. Ridley

Research output: Contribution to journalArticle

297 Scopus citations

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 μ-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 μ-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.

Original languageEnglish (US)
Pages (from-to)727-736
Number of pages10
JournalBiochemical Pharmacology
Volume55
Issue number6
DOIs
StatePublished - Mar 15 1998

Keywords

  • Drug-haematin binding
  • Haematin polymerisation
  • Haemozoin
  • Malaria
  • Quinoline antimalarials
  • μ-Oxo dimer

ASJC Scopus subject areas

  • Biochemistry
  • Pharmacology

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