A common mechanism for blockade of heme polymerization by antimalarial quinolines.
The antimalarial quinolines are believed to work by blocking the polymerization of toxic heme released during hemoglobin proteolysis in intraerythrocytic Plasmodium falciparum. In the presence of free heme, chloroquine and quinidine associate with the heme polymer. We have proposed that this association of the quinoline-heme complex with polymer caps the growing heme polymer, preventing further sequestration of additional heme that then accumulates to levels that kill the parasite. In this work results of binding assays demonstrate that the association of quinoline-heme complex with heme polymer is specific, saturable, and high affinity and that diverse quinoline analogs can compete for binding. The relative quinoline binding affinity for heme polymer rather than free heme correlates with disruption of heme polymerization. Mefloquine, another important antimalarial quinoline, associated with polymer in a similar fashion, both in cultured parasites and in the test tube. 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 action dependent on drug interaction with both heme and heme polymer.
Sullivan
D J
DJ
Department of Molecular Microbiology and Immunology, Johns Hopkins School of Hygiene and Public Health, Baltimore, Maryland 21205, USA. dsulliva@jhsph.edu
Matile
H
H
Ridley
R G
RG
Goldberg
D E
DE
D000818:Animals; D000962:Antimalarials / Q000737:chemistry / Q000378:metabolism*; D002738:Chloroquine / Q000737:chemistry / Q000378:metabolism; D004912:Erythrocytes / Q000469:parasitology; D006418:Heme / Q000737:chemistry / Q000378:metabolism*; D006420:Hemeproteins / Q000378:metabolism*; D015767:Mefloquine / Q000737:chemistry / Q000378:metabolism; D010963:Plasmodium falciparum / Q000378:metabolism*; D011108:Polymers; D011802:Quinidine / Q000737:chemistry / Q000378:metabolism; D011804:Quinolines / Q000737:chemistry / Q000378:metabolism*
D000962:Antimalarials; D006420:Hemeproteins; D011108:Polymers; D011804:Quinolines; C020753:hemozoin; D006418:Heme; D002738:Chloroquine; D011802:Quinidine; D015767:Mefloquine