Opening up the advantages of the ruthenocenic bioprobes of ferroquine: distribution and localization in Plasmodium falciparum-infected erythrocytes.
A ferrocene-quinoline conjugate named ferroquine (FQ or SSR97193) is active against both chloroquine-susceptible and chloroquine-resistant Plasmodium falciparum and P. vivax strains and/or isolates. FQ was shown to be efficient for the treatment of uncomplicated malaria in humans (phase IIb of clinical trials). However, the molecular basis of FQ's mechanism of action is still unknown because few approaches (such as radioactive labelling or immunofluorescence) are available for that purpose. Previous reports from our laboratory suggest that the intramolecular hydrogen bond in the lateral side chain plays a crucial role in the antimalarial activity of the drug. We used two ruthenocenic bioprobes of FQ (with and without an intramolecular hydrogen bond) to study their localization and quantification in Plasmodium falciparum-infected erythrocytes. We first used Inductively Coupled Plasma Mass Spectroscopy (ICP-MS) analysis to trace ruthenoquine (RQ, with an intramolecular hydrogen bond) and methylruthenoquine (Me-RQ, without an intramolecular hydrogen bond) in the infected red blood cells (iRBCs). We showed that RQ accumulates faster in the digestive vacuole of the iRBCs than Me-RQ. We next examined the ruthenium distribution at the ultrastructural level by transmission electron microscopy (TEM). We showed that RQ accumulates faster in the parasitic digestive vacuole (DV) close to its membranes than Me-RQ.
Université Lille1, Unité de Glycobiologie Structurale et Fonctionnelle, CNRS UMR 8576, IFR 147, 59650 Villeneuve d'Ascq Cédex, France. christophe.biot@univ-lille1.fr
Christophe
C
Biot
Faustine
F
Dubar
Jamal
J
Khalife
Christian
C
Slomianny
D000634:Aminoquinolines / Q000737:chemistry / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000962:Antimalarials / Q000737:chemistry / Q000493:pharmacokinetics* / Q000627:therapeutic use; D004912:Erythrocytes / Q000187:drug effects / Q000378:metabolism / Q000469:parasitology*; D005296:Ferrous Compounds / Q000737:chemistry / Q000493:pharmacokinetics* / Q000627:therapeutic use; D006801:Humans; D008288:Malaria / Q000188:drug therapy; D000075163:Metallocenes; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000302:isolation & purification; D012428:Ruthenium / Q000737:chemistry / Q000493:pharmacokinetics* / Q000627:therapeutic use
D000634:Aminoquinolines; D000962:Antimalarials; D005296:Ferrous Compounds; D000075163:Metallocenes; D012428:Ruthenium; C479230:ferroquine