Identification and characterization of the antiplasmodial activity of Hsp90 inhibitors

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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12936-017-1940-7) contains supplementary material, which is available to authorized users.

A docking-based structural analysis of geldanamycin-derived inhibitor binding to human or Leishmania Hsp90

“…Similarly to the present study, Murillo-Solano, et al . 19 demonstrated that GA, 17-AAG and 17-DMAG were able to inhibit the growth of P . falciparum at submicromolar concentrations, whereas growth inhibition in human pulmonary fibroblasts was only observed at levels over 10 μM.…”

“…More recently, Murillo-Solano, et al . 19 demonstrated that GA, 17-AAG and 17-DMAG suppressed the growth of P . falciparum at concentrations shown to be non-toxic to host cells.…”

Small Molecule Inhibitors Targeting the Heat Shock Protein System of Human Obligate Protozoan Parasites

“…So far, several natural and synthetic drugs targeting Hsp90, including natural ansamycin and derivatives of purine, resorcinol, benzamide, aminopyri(mi)dines, and tricyclic imidapyridines, have been described (Figure 2) [53,54,55]. Independent studies have evaluated the antiparasitic activity of some anticancer Hsp90 inhibitors (Figure 2), including ansamycin (GA, 17-AAG, 17-DMAG), benzamides (SNX-5422, SNX-2112), resorcinol (onalespib, luminespib, ganetesbip [STA-9090]), and a purine scaffold BIIB021, PU-H71 [56,57]. However, the main shortcoming of these anticancer agents as antiparasitic agents has been lack of selectivity between host and parasite Hsp90, resulting in hepatoxicity [58,59,60].…”

“…There have been recent efforts to repurpose anticancer Hsp90 inhibitors towards addressing several parasitic diseases, including P. falciparum malaria. Among these potentially repurposed compounds, 17-DMAG and NVP-AUY922 (luminespib) have been reported to exhibit high affinity for plasmodial Hsp90s (cytosolic PfHsp90 and ER Grp94) [55,56]. In addition, 17-DMAG and luminespib have been shown to exhibit potent cytotoxicity to chloroquine-resistant P. falciparum parasite growth [56].…”

“…Among these potentially repurposed compounds, 17-DMAG and NVP-AUY922 (luminespib) have been reported to exhibit high affinity for plasmodial Hsp90s (cytosolic PfHsp90 and ER Grp94) [55,56]. In addition, 17-DMAG and luminespib have been shown to exhibit potent cytotoxicity to chloroquine-resistant P. falciparum parasite growth [56]. However, using cell culture assays, 17-DMAG and luminespib were reported to be incapable of selectivity for parasite Hsp90 without affecting human Hsp90 [55,56,60].…”