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J Biol Chem, Vol. 273, Issue 47, 31103-31107, November 20, 1998
,
From the 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.
Department of Molecular Microbiology and
Immunology, Johns Hopkins School of Hygiene and Public Health,
Baltimore, Maryland 21205, ¶ Hoffmann-La Roche, Pharmaceuticals
Division, Pharma Research Preclinical, Basel, Switzerland, CH-4070 and
Howard Hughes Medical Institute, Departments of Medicine and
Molecular Microbiology, Washington University School of Medicine,
St. Louis, Missouri 63110
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