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Review
. 2013 Feb 4;2(1):33-54.
doi: 10.3390/pathogens2010033.

Targeting Plasmodium falciparum Hsp90: Towards Reversing Antimalarial Resistance

Dea Shahinas  1 , Asongna Folefoc  2 , Dylan R Pillai  3
Affiliations
Review

Targeting Plasmodium falciparum Hsp90: Towards Reversing Antimalarial Resistance

Dea Shahinas et al. Pathogens. .

Abstract

Malaria continues to exact a great human toll in tropical settings. Antimalarial resistance is rife and the parasite inexorably develops mechanisms to outwit our best drugs, including the now first-line choice, artesunate. Novel strategies to circumvent resistance are needed. Here we detail drug development focusing on heat shock protein 90 and its central role as a chaperone. A growing body of evidence supports the role for Hsp90 inhibitors as adjunctive drugs able to restore susceptibility to traditionally efficacious compounds like chloroquine.

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Figures

Figure 1
Figure 1
An illustration of the intra-erythrocytic cycle of Plasmodium falciparum. The infection of a red blood cell (RBC) during one intra-erythrocytic cycle is depicted. The inset pictures were taken under a light microscope and show the appearance of the parasites at the different stages upon Giemsa staining. One cycle of P. falciparum typically takes 48 h to complete.
Figure 2
Figure 2
Illustration of the localization of human and malaria Hsp90 paralogs inside a red blood cell (RBC) infected with P.falciparum. The focus of this review is on PfHsp90 (PF07_0029), which is the cytosolic isoform with a conserved EEVD motif.
Figure 3
Figure 3
Two-dimensional representation of the chemical structures of the Hsp90 inhibitors discussed in this review: geldanamycin (GA), 17-AAG, PU-H71 and harmine. The structures were generated using Jchempaint [83].
Figure 4
Figure 4
Illustration of the emerging cellular model of PfHsp90 inhibitors and CQ in CQ-sensitive (CQS) and CQ-resistant (CQR) P.falciparum infected RBCs. Drug application introduces pharmacological stress, which may result in activation of the PfHsp90 chaperone machinery. CQ accumulation in the digestive vacuole inhibits the detoxification of hemoglobin byproducts in CQS, but not CQR parasites. Inhibition of PfHsp90 chemosensitizes the cells by an arrest of folding clients involved in detoxification, multiple drug resistance and virulence factors. CQS: CQ sensitive CQR: CQ resistant.
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