On the mechanism of chloroquine resistance in Plasmodium falciparum.

Chinappi, Mauro; Via, Allegra; Marcatili, Paolo; Tramontano, Anna

On the mechanism of chloroquine resistance in Plasmodium falciparum.

Files

PMC2988812.pdf (2.98 MB)

Type

Article

Authors

Chinappi, Mauro
Via, Allegra
Marcatili, Paolo
Tramontano, Anna

KAUST Grant Number

KUK-I1-012-43

Date

2010-11-19

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.

Acknowledgements

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.