Deciphering the resistance-counteracting functions of the antimalarial ferroquine in Plasmodium falciparum-infected erythrocytes
Identifieur interne : 000211 ( France/Analysis ); précédent : 000210; suivant : 000212Deciphering the resistance-counteracting functions of the antimalarial ferroquine in Plasmodium falciparum-infected erythrocytes
Auteurs : Faustine Dubar [France] ; Sylvain Bohic [France] ; Daniel Dive [France] ; Yann Guérardel [France] ; Peter Cloetens [France] ; Jamal Khalife [France] ; Christophe Biot [France]Source :
- ACS Medicinal Chemistry Letters [ 1948-5875 ] ; 2012-07-20.
English descriptors
Abstract
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.
Url:
DOI: 10.1021/ml300062q
Affiliations:
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Hal:inserm-00739069Le document en format XML
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<idno type="DOI">10.1021/ml300062q</idno>
<series><title level="j">ACS Medicinal Chemistry Letters</title>
<idno type="ISSN">1948-5875</idno>
<imprint><date type="datePub">2012-07-20</date>
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<profileDesc><textClass><keywords scheme="mix" xml:lang="en"><term>antiparasitic agents</term>
<term>chloroquine</term>
<term>drug delivery</term>
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<front><div type="abstract" xml:lang="en"> <p>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.</p>
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</country>
<region><li>Auvergne-Rhône-Alpes</li>
<li>Rhône-Alpes</li>
</region>
<settlement><li>Grenoble</li>
</settlement>
<orgName><li>Université Joseph Fourier</li>
<li>Université de Grenoble</li>
</orgName>
</list>
<tree><country name="France"><noRegion><name sortKey="Dubar, Faustine" sort="Dubar, Faustine" uniqKey="Dubar F" first="Faustine" last="Dubar">Faustine Dubar</name>
</noRegion>
<name sortKey="Biot, Christophe" sort="Biot, Christophe" uniqKey="Biot C" first="Christophe" last="Biot">Christophe Biot</name>
<name sortKey="Bohic, Sylvain" sort="Bohic, Sylvain" uniqKey="Bohic S" first="Sylvain" last="Bohic">Sylvain Bohic</name>
<name sortKey="Cloetens, Peter" sort="Cloetens, Peter" uniqKey="Cloetens P" first="Peter" last="Cloetens">Peter Cloetens</name>
<name sortKey="Dive, Daniel" sort="Dive, Daniel" uniqKey="Dive D" first="Daniel" last="Dive">Daniel Dive</name>
<name sortKey="Guerardel, Yann" sort="Guerardel, Yann" uniqKey="Guerardel Y" first="Yann" last="Guérardel">Yann Guérardel</name>
<name sortKey="Khalife, Jamal" sort="Khalife, Jamal" uniqKey="Khalife J" first="Jamal" last="Khalife">Jamal Khalife</name>
</country>
</tree>
</affiliations>
</record>
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