Interference with heme binding to histidine-rich protein-2 as an antimalarial strategy.
The erythrocytic growth stage of Plasmodium falciparum involves hemoglobin proteolysis as the primary nutrient source with the concomitant release of free heme. The liberated heme is processed by the parasite into hemozoin, a polymeric porphyrin dimer. Histidine-rich protein binds heme and mediates the formation of hemozoin, which is inhibited by the antimalarial drug chloroquine. Interference with heme binding was determined using a microtiterplate assay. Combinatorial libraries were screened and tested against parasite growth, revealing a good correlation between heme binding interference and the inhibition of parasite growth. Several of these compounds retain their potency against a chloroquine-resistant strain of Plasmodium falciparum. The most potent compounds have IC(50) values less than or equal to 50 nM against chloroquine-resistant and chloroquine-sensitive parasites.
Department of Biological Chemistry, Howard Hughes Medical Institute, Ann Arbor, MI 48109, USA.
Clara Y H
CY
Choi
Eric L
EL
Schneider
Jin M
JM
Kim
Ilya Y
IY
Gluzman
Daniel E
DE
Goldberg
Jonathan A
JA
Ellman
Michael A
MA
Marletta
D000818:Animals; D000962:Antimalarials / Q000737:chemistry* / Q000494:pharmacology; D020650:Combinatorial Chemistry Techniques; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D006418:Heme / Q000378:metabolism*; D020128:Inhibitory Concentration 50; D010963:Plasmodium falciparum / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D011506:Proteins / Q000378:metabolism*; D015800:Protozoan Proteins / Q000378:metabolism; D013329:Structure-Activity Relationship; D000099053:Histidine-Rich Glycoprotein
D000962:Antimalarials; D011506:Proteins; D015800:Protozoan Proteins; D000099053:Histidine-Rich Glycoprotein; D006418:Heme