Abstract
BackgroundThe recent reduction in mortality due to malaria is being threatened by the appearance of Plasmodium falciparum parasites that are resistant to artemisinin in Southeast Asia. To limit the impact of resistant parasites and their spread across the world, there is a need to validate anti-malarial drug targets and identify new leads that will serve as foundations for future drug development programmes targeting malaria. Towards that end, the antiplasmodial potential of several Hsp90 inhibitors was characterized. Because, the Hsp90 chaperone has been suggested as a good drug target against multiple parasitic infections including malaria.ResultsChemically diverse sets of Hsp90 inhibitors, evaluated in clinical trials as anti-cancer agents, were tested against the malaria parasite. Most of the compounds showed strong antiplasmodial activity in growth inhibition assays against chloroquine sensitive and resistant strains. There was a good agreement between the compound in vitro anti-parasitic activity and their affinity against the Plasmodium chaperone. The two most potent Hsp90 inhibitors also showed cytocidal activity against two P. falciparum strains. Their antiplasmodial activity affected all parasite forms during the malaria blood cycle. However, the compounds activity against the parasite showed no synergy when combined with anti-malarial drugs, like chloroquine or DHA.DiscussionThe Hsp90 inhibitors anti-parasitic activity correlates with their affinity to their predicted target the P. falciparum chaperone Hsp90. However, the most effective compounds also showed high affinity for a close homologue, Grp94. This association points to a mode of action for Hsp90 inhibitors that correlate compound efficacy with multi-target engagement. Besides their ability to limit parasite replication, two compounds also significantly impacted P. falciparum viability in vitro. Finally, a structural analysis suggests that the best hit represents a promising scaffold to develop parasite specific leads according.ConclusionThe results shown that Hsp90 inhibitors are lethal against the malaria parasite. The correlation between biochemical and in vitro data strongly supports Hsp90 as a drug target against the malaria parasite. Furthermore, at least one Hsp90 inhibitor developed as anticancer therapeutics could serve as starting point to generate P. falciparum-specific lead compounds.
Highlights
The recent reduction in mortality due to malaria is being threatened by the appearance of Plasmodium falciparum parasites that are resistant to artemisinin in Southeast Asia
heat shock protein 90 (Hsp90) inhibitors The Hsp90 inhibitors selected belong to three different scaffolds (Fig. 1): first, the ansamycin represented by geldanamycin [24], 17-AAG [25] and 17-DMAG [26]; second, the benzamides included SNX-5422 and SNX2112 [27]; third, the resorcinol that included AT13387 [28], NVP-AUY922 [29], and STA-9090 [30]; and fourth, the purine scaffold that included compounds PUH71 and PUSW13 [31, 32]
Malaria parasite susceptibility to Hsp90 inhibitors The eight Hsp90 inhibitors that were tested strongly suppressed parasite growth and six of them showed an IC50 in the submicromolar range (Table 1; Additional file 1: Figure S1 for normalized dose response graphs)
Summary
The chaperone is a homodimer associated via its C-terminal or dimerization domains, and its middle or substratebinding domain assists in the final folding stage of nascent proteins [7] These Hsp substrates are called clients and represent ~5% of the cell proteome, including protein kinases, phosphatases and transcription factors that require chaperone assistance to reach their active state [8]. Many of the Hsp clients are essential proteins involved in multiple cell regulatory processes and required for the survival of the cell [9] This keystone position of Hsp explains the essentiality of this chaperone in eukaryotes. The conformational changes linking the ATPase and chaperone activities are called the Hsp catalytic cycle [7] This connection allows ATP competitive inhibitors to limit its chaperone function, thereby affecting the concentration of Hsp clients [11]. These Hsp inhibitors are toxic to cells and organisms that heavily depend on the Hsp chaperone function, such as cancer cells or parasites [12, 13]
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