An Assessment of Drug-Haematin Binding as a Mechanism for Inhibition of Haematin Polymerisation by Quinoline Antimalarials

doi:10.1016/S0006-2952(97)00510-8

Biochemical Pharmacology

Volume 55, Issue 6, 15 March 1998, Pages 727-736

https://doi.org/10.1016/S0006-2952(97)00510-8 Get rights and content

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.

Section snippets

Compounds

All compounds for this study were obtained from the Hoffmann–La Roche inventory. They included the blood schizonticides chloroquine, quinacrine, amodiaquine, pyronaridine, quinine, mefloquine, halofantrine, and a bisquinoline, Ro 48-6910, trans-N¹,N²-bis(7-chloro-quinolin-4-yl)cyclohexane-1,2-diamine 15, 16. Primaquine [17], an 8-aminoquinoline which is inactive against blood stage parasites and hence unlikely to interfere with haemozoin formation, but which is active against liver stage

Correlation between Inhibition of Haematin Polymerisation and Inhibition of Parasite Growth in Culture

We tested compounds against a strain highly susceptible to quinoline antimalarials, namely P. falciparum NF54. We compared these values with the ic₅₀ values for compound inhibition of haematin polymerisation at pH 4.8, which approximates to the pH of the food vacuole in the parasite. The results, shown in Fig. 2, demonstrate that there is a good correlation between hematin polymerisation inhibition and parasite growth inhibition for quinoline-containing blood schizonticides (r = 0.91, P =

Discussion

The results presented here build on our earlier hypothesis that haematin polymerisation is not enzyme-dependent and that quinoline-containing antimalarials most likely exert their activity through direct interaction with haematin [10], as previously proposed by Fitch [14].

Acknowledgements

This investigation received some financial support from the UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases (to JLV).

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Research PapersAn Assessment of Drug-Haematin Binding as a Mechanism for Inhibition of Haematin Polymerisation by Quinoline Antimalarials

Abstract

Section snippets

Compounds

Correlation between Inhibition of Haematin Polymerisation and Inhibition of Parasite Growth in Culture

Discussion

Acknowledgements

Parasitol Today

Parasitol Today

J Biol Chem

FEBS Lett

Trends Microbiol

Biochem Pharmacol

Prog Med Chem

Trans Royal Soc Trop Med Hyg

Anal Biochem

Inorg Chim Acta

Biochem Biophys Res Comm

Biochimie

Biophys Chem

Mol Biochem Parasitol

Biochem Pharmacol

Biochem Pharmacol

Biol Cell

Chem Biol Interactions

Biochem Pharmacol

Biochim Biophys Acta

Biochem Pharm

J Inorg Biochem

Pharmacol Ther

Biochem Biophys Res Comm

Biochim Biophys Acta

Heme catabolism by heme oxygenasephysiology, regulation, and mechanism of action

Semin Hematol

An iron-carboxylate bond links the heme units of malaria pigment

Proc Natl Acad Sci USA

Spectroscopic investigations of malaria pigment

Appl Spectroscopy

Research Papers
An Assessment of Drug-Haematin Binding as a Mechanism for Inhibition of Haematin Polymerisation by Quinoline Antimalarials