Malaria Pigment Crystals: The Achilles ' Heel of the Malaria Parasite
Publikation: Bidrag til tidsskrift › Review › Forskning › fagfællebedømt
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Malaria Pigment Crystals : The Achilles ' Heel of the Malaria Parasite. / Kapishnikov, Sergey; Hempelmann, Ernst; Elbaum, Michael; Als-Nielsen, Jens; Leiserowitz, Leslie.
I: ChemMedChem, 19.03.2021.Publikation: Bidrag til tidsskrift › Review › Forskning › fagfællebedømt
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TY - JOUR
T1 - Malaria Pigment Crystals
T2 - The Achilles ' Heel of the Malaria Parasite
AU - Kapishnikov, Sergey
AU - Hempelmann, Ernst
AU - Elbaum, Michael
AU - Als-Nielsen, Jens
AU - Leiserowitz, Leslie
PY - 2021/3/19
Y1 - 2021/3/19
N2 - The biogenic formation of hemozoin crystals, a crucial process in heme detoxification by the malaria parasite, is reviewed as an antimalarial drug target. We first focus on the in-vivo formation of hemozoin. A model is presented, based on native-contrast 3D imaging obtained by X-ray and electron microscopy, that hemozoin nucleates at the inner membrane leaflet of the parasitic digestive vacuole, and grows in the adjacent aqueous medium. Having observed quantities of hemoglobin and hemozoin in the digestive vacuole, we present a model that heme liberation from hemoglobin and hemozoin formation is an assembly-line process. The crystallization is preceded by reaction between heme monomers yielding hematin dimers involving fewer types of isomers than in synthetic hemozoin; this is indicative of protein-induced dimerization. Models of antimalarial drugs binding onto hemozoin surfaces are reviewed. This is followed by a description of bromoquine, a chloroquine drug analogue, capping a significant fraction of hemozoin surfaces within the digestive vacuole and accumulation of the drug, presumably a bromoquine-hematin complex, at the vacuole's membrane.
AB - The biogenic formation of hemozoin crystals, a crucial process in heme detoxification by the malaria parasite, is reviewed as an antimalarial drug target. We first focus on the in-vivo formation of hemozoin. A model is presented, based on native-contrast 3D imaging obtained by X-ray and electron microscopy, that hemozoin nucleates at the inner membrane leaflet of the parasitic digestive vacuole, and grows in the adjacent aqueous medium. Having observed quantities of hemoglobin and hemozoin in the digestive vacuole, we present a model that heme liberation from hemoglobin and hemozoin formation is an assembly-line process. The crystallization is preceded by reaction between heme monomers yielding hematin dimers involving fewer types of isomers than in synthetic hemozoin; this is indicative of protein-induced dimerization. Models of antimalarial drugs binding onto hemozoin surfaces are reviewed. This is followed by a description of bromoquine, a chloroquine drug analogue, capping a significant fraction of hemozoin surfaces within the digestive vacuole and accumulation of the drug, presumably a bromoquine-hematin complex, at the vacuole's membrane.
KW - crystal growth
KW - crystal structure
KW - malaria
KW - hemozoin nucleation
KW - mode of action
KW - X-ray imaging
U2 - 10.1002/cmdc.202000895
DO - 10.1002/cmdc.202000895
M3 - Review
C2 - 33523575
JO - Farmaco
JF - Farmaco
SN - 1860-7179
ER -
ID: 259054585