AN ASSESSMENT OF DRUG-HEMATIN BINDING AS A MECHANISM FOR INHIBITION OF HEMATIN POLYMERIZATION BY QUINOLINE ANTIMALARIALS

Chloroquine is thought to exert its antimalarial activity by preventin g the polymerisation of toxic haematin released during proteolysis of haemoglobin in the Plasmodium digestive vacuole. However, the molecula r mechanisms by which this inhibition occurs and the universality of t his mechanism for other quinoline antimalarials remain to be establish ed. We demonstrate here a correlation for eight antimalarial quinoline s between inhibition of haematin polymerisation in vitro and inhibitio n of P. falciparum growth in culture, confirming haematin polymerisati on as the likely target of quinoline blood schizonticides. Furthermore , using isothermal titration microcalorimetry, a correlation was obser ved between the haematin binding constant of these compounds and their ability to inhibit haematin polymerisation, suggesting that these com pounds mediate their activity through binding to haematin. It was also observed that the compounds bind primarily to the mu-oxo dimer form o f haematin rather than the monomeric form. It is postulated that this binding inhibits haematin polymerisation by shifting the haematin dime risation equilibrium to the CL-oxo dimer, thus reducing the availabili ty 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. (C) 1998 Elsevier Science Inc.