On the mechanism of chloroquine resistance in Plasmodium falciparum.

Handle URI:
http://hdl.handle.net/10754/596846
Title:
On the mechanism of chloroquine resistance in Plasmodium falciparum.
Authors:
Chinappi, Mauro; Via, Allegra; Marcatili, Paolo; Tramontano, Anna
Abstract:
Resistance to chloroquine of malaria strains is known to be associated with a parasite protein named PfCRT, the mutated form of which is able to reduce chloroquine accumulation in the digestive vacuole of the pathogen. Whether the protein mediates extrusion of the drug acting as a channel or as a carrier and which is the protonation state of its chloroquine substrate is the subject of a scientific debate. We present here an analytical approach that explores which combination of hypotheses on the mechanism of transport and the protonation state of chloroquine are consistent with available equilibrium experimental data. We show that the available experimental data are not, by themselves, sufficient to conclude whether the protein acts as a channel or as a transporter, which explains the origin of their different interpretation by different authors. Interestingly, though, each of the two models is only consistent with a subset of hypotheses on the protonation state of the transported molecule. The combination of these results with a sequence and structure analysis of PfCRT, which strongly suggests that the molecule is a carrier, indicates that the transported species is either or both the mono and di-protonated forms of chloroquine. We believe that our results, besides shedding light on the mechanism of chloroquine resistance in P. falciparum, have implications for the development of novel therapies against resistant malaria strains and demonstrate the usefulness of an approach combining systems biology strategies with structural bioinformatics and experimental data.
Citation:
Chinappi M, Via A, Marcatili P, Tramontano A (2010) On the Mechanism of Chloroquine Resistance in Plasmodium falciparum. PLoS ONE 5: e14064. Available: http://dx.doi.org/10.1371/journal.pone.0014064.
Publisher:
Public Library of Science (PLoS)
Journal:
PLoS ONE
KAUST Grant Number:
KUK-I1-012-43
Issue Date:
19-Nov-2010
DOI:
10.1371/journal.pone.0014064
PubMed ID:
21124966
PubMed Central ID:
PMC2988812
Type:
Article
ISSN:
1932-6203
Sponsors:
This work was supported by King Abdullah University of Science and Technology (KAUST) - Award No. KUK-I1-012-43 (http://www.kaust.edu.sa/), Human Frontier Science Program (HFSP) -RGP0054/2006-C grant (http://www.hfsp.org/), and Fondazione Roma (http://www.fondazioneroma.it/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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Full metadata record

DC FieldValue Language
dc.contributor.authorChinappi, Mauroen
dc.contributor.authorVia, Allegraen
dc.contributor.authorMarcatili, Paoloen
dc.contributor.authorTramontano, Annaen
dc.date.accessioned2016-02-21T09:35:17Zen
dc.date.available2016-02-21T09:35:17Zen
dc.date.issued2010-11-19en
dc.identifier.citationChinappi M, Via A, Marcatili P, Tramontano A (2010) On the Mechanism of Chloroquine Resistance in Plasmodium falciparum. PLoS ONE 5: e14064. Available: http://dx.doi.org/10.1371/journal.pone.0014064.en
dc.identifier.issn1932-6203en
dc.identifier.pmid21124966en
dc.identifier.doi10.1371/journal.pone.0014064en
dc.identifier.urihttp://hdl.handle.net/10754/596846en
dc.description.abstractResistance to chloroquine of malaria strains is known to be associated with a parasite protein named PfCRT, the mutated form of which is able to reduce chloroquine accumulation in the digestive vacuole of the pathogen. Whether the protein mediates extrusion of the drug acting as a channel or as a carrier and which is the protonation state of its chloroquine substrate is the subject of a scientific debate. We present here an analytical approach that explores which combination of hypotheses on the mechanism of transport and the protonation state of chloroquine are consistent with available equilibrium experimental data. We show that the available experimental data are not, by themselves, sufficient to conclude whether the protein acts as a channel or as a transporter, which explains the origin of their different interpretation by different authors. Interestingly, though, each of the two models is only consistent with a subset of hypotheses on the protonation state of the transported molecule. The combination of these results with a sequence and structure analysis of PfCRT, which strongly suggests that the molecule is a carrier, indicates that the transported species is either or both the mono and di-protonated forms of chloroquine. We believe that our results, besides shedding light on the mechanism of chloroquine resistance in P. falciparum, have implications for the development of novel therapies against resistant malaria strains and demonstrate the usefulness of an approach combining systems biology strategies with structural bioinformatics and experimental data.en
dc.description.sponsorshipThis work was supported by King Abdullah University of Science and Technology (KAUST) - Award No. KUK-I1-012-43 (http://www.kaust.edu.sa/), Human Frontier Science Program (HFSP) -RGP0054/2006-C grant (http://www.hfsp.org/), and Fondazione Roma (http://www.fondazioneroma.it/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.en
dc.publisherPublic Library of Science (PLoS)en
dc.rightsThis is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.en
dc.subject.meshAlgorithmsen
dc.subject.meshModels, Biologicalen
dc.titleOn the mechanism of chloroquine resistance in Plasmodium falciparum.en
dc.typeArticleen
dc.identifier.journalPLoS ONEen
dc.identifier.pmcidPMC2988812en
dc.contributor.institutionUniversita degli Studi di Roma La Sapienza, Rome, Italyen
dc.contributor.institutionUniversita degli Studi di Roma La Sapienza, Rome, Italyen
kaust.grant.numberKUK-I1-012-43en
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