Lipophilic Bisphosphonates Are Potent Inhibitors of Plasmodium Liver-Stage Growth

DOI: 10.1128/AAC.00198-10

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FIG. 1.
Schematic illustration of isoprenoid biosynthesis pathways (in humans and Plasmodium spp.) and sites of action of several inhibitors. Malaria parasites make IPP and DMAPP via the nonmevalonate pathway. Inhibition of isoprenoid biosynthesis affects protein prenylation; IPP buildup activates γδ (gd) T cells; and IPP is converted to toxic ATP analogs on FPPS inhibition. ANT, adenine nucleotide translocase; DXP, 1-deoxy-d-xylulose 5-phosphate; MEP, 2-C-methyl-d-erythritol 4-phosphate; HMG, 3-hydroxy-3-methyl-glutaryl-CoA; TNF-α, tumor necrosis factor alpha; IFN-γ, gamma interferon.
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FIG. 2.
Structures of the inhibitors tested.
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FIG. 3.
Typical dose-response curves for in vitro activity of two bisphosphonates, BPH-715 (A) and risedronate (B), versus Plasmodium berghei EEF cell growth inhibition.
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FIG. 4.
Results showing growth of untreated (A) and treated (B) (30 μM BPH-715) EEFs at 50 h postinfection with sporozoites. EEFs were visualized by immunofluorescence assay using anti-HSP70 (parasite protein) monoclonal antibody as the primary antibody and anti-mouse IgG Alexa 594 as the secondary antibody. BPH-715-treated EEFs show severe growth defects. Bars, 10 μm. (C) Area measurements of treated and untreated EEFs at 50 h postinfection with sporozoites.

TABLE 4.

Enzyme inhibition for Plasmodium vivax GGPPS, human FPPS, and human GGPPS, together with SlogP values

↵ a Measured as described in reference 12.
↵ b Measured as described in reference 15.
↵ c Measured as described in reference 21.
↵ d Calculated using the MOE program (Molecular Operating Environment 2006.08; Chemical Computing Group, Inc., Montreal, Quebec, Canada).
↵ e K_i, inhibition constant.