Digeranyl bisphosphonate inhibits geranylgeranyl pyrophosphate synthase

Wiemer, Andrew J.; Tong, Hao; Swanson, Kelly M.; Hohl, Raymond J.

doi:10.1016/j.bbrc.2006.12.094

Cited by 71 publications

(78 citation statements)

References 23 publications

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“…Bisphosphonates, including risedronate and zoledronate, are widely used to prevent and treat osteoporosis and have been shown to inhibit FPPS in many organisms, including humans (25) and some parasites (26). Digeranyl bisphosphonates are known to inhibit human GGPPS (46). No studies have been done on schistosome FPPS or GGPPS or on the activity of bisphosphonates against schistosomes.…”

Section: Discussionmentioning

confidence: 99%

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Characterization of Potential Drug Targets Farnesyl Diphosphate Synthase and Geranylgeranyl Diphosphate Synthase in Schistosoma mansoni

Ziniel

Desai

Cass

et al. 2013

Antimicrob Agents Chemother

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dSchistosomiasis affects over 200 million people worldwide, with over 200,000 deaths annually. Currently, praziquantel is the only drug available against schistosomiasis. We report here that Schistosoma mansoni farnesyl diphosphate synthase (SmFPPS) and geranylgeranyl diphosphate synthase (SmGGPPS) are potential drug targets for the treatment of schistosomiasis. We expressed active, recombinant SmFPPS and SmGGPPS for subsequent kinetic characterization and testing against a variety of bisphosphonate inhibitors. Recombinant SmFPPS was found to be a soluble 44.2-kDa protein, while SmGGPPS was a soluble 38.3-kDa protein. Characterization of the substrate utilization of the two enzymes indicates that they have overlapping substrate specificities. Against SmFPPS, several bisphosphonates had 50% inhibitory concentrations (IC 50 s) in the low micromolar to nanomolar range; these inhibitors had significantly less activity against SmGGPPS. Several lipophilic bisphosphonates were active against ex vivo adult worms, with worm death occurring over 4 to 6 days. These results indicate that FPPS and GGPPS could be of interest in the context of the emerging resistance to praziquantel in schistosomiasis therapy.

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Section: Discussionmentioning

confidence: 99%

“…For instance, the active sites of both proteins typically contain two "aspartate-rich" motifs (40,46). These are both present in the amino acid sequences of SmFPPS and SmGGPPS.…”

Section: Discussionmentioning

confidence: 99%

Characterization of Potential Drug Targets Farnesyl Diphosphate Synthase and Geranylgeranyl Diphosphate Synthase in Schistosoma mansoni

Ziniel

Desai

Cass

et al. 2013

Antimicrob Agents Chemother

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“…1), which was found to have an IC 50 of 260 nM against the enzyme (Shull et al, 2006;Wiemer et al, 2007). Crystallography studies revealed that the V-shaped compound occupied the FDP substrate binding site as well as the GGDP product site within the enzyme's active site (K-M Chen et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Olefin Isomers of a Triazole Bisphosphonate Synergistically Inhibit Geranylgeranyl Diphosphate Synthase

et al. 2017

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The isoprenoid donor for protein geranylgeranylation reactions, geranylgeranyl diphosphate (GGDP), is the product of the enzyme GGDP synthase (GGDPS) that condenses farnesyl diphosphate (FDP) and isopentenyl pyrophosphate. GGDPS inhibition is of interest from a therapeutic perspective for multiple myeloma because we have shown that targeting Rab GTPase geranylgeranylation impairs monoclonal protein trafficking, leading to endoplasmic reticulum stress and apoptosis. We reported a series of triazole bisphosphonate GGDPS inhibitors, of which the most potent was a 3:1 mixture of homogeranyl (HG) and homoneryl (HN) isomers. Here we determined the activity of the individual olefin isomers. Enzymatic and cellular assays revealed that although HN is approximately threefold more potent than HG, HN is not more potent than the original mixture. Studies in which cells were treated with varying concentrations of each isomer alone and in different combinations revealed that the two isomers potentiate the induced-inhibition of protein geranylgeranylation when used in a 3:1 HG:HN combination. A synergistic interaction was observed between the two isomers in the GGDPS enzyme assay. These results suggested that the two isomers bind simultaneously to the enzyme but within different domains. Computational modeling studies revealed that HN is preferred at the FDP site, that HG is preferred at the GGDP site, and that both isomers may bind to the enzyme simultaneously. These studies are the first to report a set of olefin isomers that synergistically inhibit GGDPS, thus establishing a new paradigm for the future development of GGDPS inhibitors.

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“…4 Thus, it can be argued that inhibitors of GGDPS may be a more direct means to the biological effects desired from FDPS inhibitors and that they might have clinical value. 3 Some years ago we reported the preparation of digeranyl bisphosphonate (DGBP, 4) 5 and its identification as a selective 6 and reasonably potent inhibitor of GGDPS (IC 50 ≈ 0.2 μM).…”

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confidence: 99%

Potent Triazole Bisphosphonate Inhibitor of Geranylgeranyl Diphosphate Synthase

Wills

Allen

Holstein

et al. 2015

ACS Med. Chem. Lett.

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Studies of triazole bisphosphonates have resulted in identification of a potent inhibitor of geranylgeranyl diphosphate synthase (IC 50 = 45 nM) with very good selectivity for this enzyme over farnesyl diphosphate synthase (IC 50 = 28 μM). This compound also potently disrupts geranylgeranylation and induces cytotoxicity in human myeloma cells at submicromolar levels, suggesting that it may serve as a lead compound for treatment of malignancies characterized by excessive protein secretion.

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Digeranyl bisphosphonate inhibits geranylgeranyl pyrophosphate synthase

Cited by 71 publications

References 23 publications

Characterization of Potential Drug Targets Farnesyl Diphosphate Synthase and Geranylgeranyl Diphosphate Synthase in Schistosoma mansoni

Characterization of Potential Drug Targets Farnesyl Diphosphate Synthase and Geranylgeranyl Diphosphate Synthase in Schistosoma mansoni

Olefin Isomers of a Triazole Bisphosphonate Synergistically Inhibit Geranylgeranyl Diphosphate Synthase

Potent Triazole Bisphosphonate Inhibitor of Geranylgeranyl Diphosphate Synthase

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