Deciphering the resistance-counteracting ...
Document type :
Article dans une revue scientifique: Article original
DOI :
Title :
Deciphering the resistance-counteracting functions of the antimalarial ferroquine in Plasmodium falciparum-infected erythrocytes
Author(s) :
Dubar, Faustine [Auteur]
Unité de Catalyse et Chimie du Solide - UMR 8181 [UCCS]
Bohic, Sylvain [Auteur]
Dive, Daniel [Auteur]
Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 [CIIL]
Guerardel, Yann [Auteur]
Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 [UGSF]
Cloetens, Peter [Auteur]
European Synchrotron Radiation Facility [ESRF]
Khalife, Jamal [Auteur]
Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 [CIIL]
Biot, Christophe [Auteur correspondant]
Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 [UGSF]

Unité de Catalyse et Chimie du Solide - UMR 8181 [UCCS]
Bohic, Sylvain [Auteur]
Dive, Daniel [Auteur]
Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 [CIIL]
Guerardel, Yann [Auteur]

Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 [UGSF]
Cloetens, Peter [Auteur]
European Synchrotron Radiation Facility [ESRF]
Khalife, Jamal [Auteur]

Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 [CIIL]
Biot, Christophe [Auteur correspondant]

Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 [UGSF]
Journal title :
ACS Medicinal Chemistry Letters
Pages :
480-483
Publisher :
American Chemical Society
Publication date :
2012-07-20
ISSN :
1948-5875
English keyword(s) :
chloroquine
drug delivery
drug resistance
antiparasitic agents
ferroquine
drug delivery
drug resistance
antiparasitic agents
ferroquine
HAL domain(s) :
Sciences du Vivant [q-bio]/Sciences pharmaceutiques
English abstract : [en]
he aminoquinoline chloroquine (CO) has been widely used for treating malaria since World War II. Resistance to CQ began to spread around 1957 and is now found in all malarious areas of the world. CQ resistance is caused ...
Show more >he aminoquinoline chloroquine (CO) has been widely used for treating malaria since World War II. Resistance to CQ began to spread around 1957 and is now found in all malarious areas of the world. CQ resistance is caused by multiple mutations in the Plasmodium falciparum chloroquine resistance transporter (PfCRT). These mutations result in an increased efflux of CQ from the acidic digestive vacuole (DV) to the cytosol of the parasite. This year, we proposed a strategy to locate and quantify the aminoquinolines in situ within infected red blood cells (iRBCs) using synchrotron based X-ray nanoprobe fluorescence. Direct measurements of unlabeled CQ and ferroquine (FQ) (a ferrocene-CQ conjugate, extremely active against CQ-resistant strains) enabled us to evidence fundamentally different transport mechanisms from the cytosol to the DV between CQ and FQ in the CQ:susceptible strain HB3. These results inspired the present study of the localization of CQ and FQ in the CQ:resistant strain W2. The introduction of the ferrocene core in the lateral side chain of CQ has an important consequence: the transporter is unable to efflux FQ from the DV. We also found that resistant parasites treated by FQ accumulate a sulfur-containing compound, credibly glutathion, in their DV.Show less >
Show more >he aminoquinoline chloroquine (CO) has been widely used for treating malaria since World War II. Resistance to CQ began to spread around 1957 and is now found in all malarious areas of the world. CQ resistance is caused by multiple mutations in the Plasmodium falciparum chloroquine resistance transporter (PfCRT). These mutations result in an increased efflux of CQ from the acidic digestive vacuole (DV) to the cytosol of the parasite. This year, we proposed a strategy to locate and quantify the aminoquinolines in situ within infected red blood cells (iRBCs) using synchrotron based X-ray nanoprobe fluorescence. Direct measurements of unlabeled CQ and ferroquine (FQ) (a ferrocene-CQ conjugate, extremely active against CQ-resistant strains) enabled us to evidence fundamentally different transport mechanisms from the cytosol to the DV between CQ and FQ in the CQ:susceptible strain HB3. These results inspired the present study of the localization of CQ and FQ in the CQ:resistant strain W2. The introduction of the ferrocene core in the lateral side chain of CQ has an important consequence: the transporter is unable to efflux FQ from the DV. We also found that resistant parasites treated by FQ accumulate a sulfur-containing compound, credibly glutathion, in their DV.Show less >
Language :
Anglais
Peer reviewed article :
Oui
Audience :
Internationale
Popular science :
Non
Source :
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