On the Mechanism of Chloroquine Resistance in Plasmodium falciparum

Mauro Chinappi, Allegra Via, Paolo Marcatili, Anna Tramontano

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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.
Original languageEnglish
Article numbere14064
JournalP L o S One
Volume5
Issue number11
Number of pages12
ISSN1932-6203
DOIs
Publication statusPublished - 2010
Externally publishedYes

Bibliographical note

This 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.

Keywords

  • drug resistance
  • structural bioinformatics
  • systems biology strategy
  • malaria Malaria (MeSH) blood and lymphatic disease, parasitic disease drug therapy
  • Protozoa Invertebrata Animalia (Animals, Invertebrates, Microorganisms, Protozoans) - Sporozoa [35400] Plasmodium falciparum species parasite strain-Dd2, strain-GC03
  • channel
  • chloroquine 54-05-7 antiinfective-drug, antiparasitic-drug pharmacodynamics
  • drug transporter
  • metabolite transporter
  • PfCRT protein
  • 04500, Mathematical biology and statistical methods
  • 10060, Biochemistry studies - General
  • 10515, Biophysics - Biocybernetics
  • 12512, Pathology - Therapy
  • 15002, Blood - Blood and lymph studies
  • 15004, Blood - Blood cell studies
  • 15006, Blood - Blood, lymphatic and reticuloendothelial pathologies
  • 22002, Pharmacology - General
  • 38502, Chemotherapy - General, methods and metabolism
  • 38510, Chemotherapy - Antiparasitic agents
  • 60502, Parasitology - General
  • 64002, Invertebrata: comparative, experimental morphology, physiology and pathology - Protozoa
  • Computational Biology
  • Transport and Circulation
  • sequence analysis laboratory techniques, genetic techniques
  • structure analysis laboratory techniques
  • three-dimensional model mathematical and computer techniques
  • Biochemistry and Molecular Biophysics
  • Blood and Lymphatics
  • Models and Simulations
  • Parasitology
  • Pharmacology

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