A COMMON MECHANISM FOR BLOCKADE OF HEME POLYMERIZATION BY ANTIMALARIAL QUINOLINES

The antimalarial quinolines are believed to work by blocking the polym erization of toxic heme released during hemoglobin proteolysis in intr aerythrocytic Plasmodium falciparum. In the presence of free heme, chl oroquine and quinidine associate with the heme polymer. We, have propo sed that this association of the quinolineheme complex with polymer ca ps the growing heme polymer, preventing further sequestration of addit ional heme that then accumulates to levels that kill the parasite. In this work results of binding assays demonstrate that the association o f quinoline-heme complex with heme polymer is specific, saturable, and high affinity and that diverse quinoline analogs can compete for bind ing. The relative quinoline binding affinity for heme polymer rather t han free heme correlates with disruption of heme polymerization. Meflo quine, another important antimalarial quinoline, associated with polym er in a similar fashion, both in cultured parasites and in the test tu be. In parasite culture, blocking heme release with protease inhibitor was antagonistic to mefloquine action, as it is to chloroquine action . These data suggest a common mechanism for quinoline antimalarial act ion dependent on drug interaction with both heme and heme polymer.