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

Abstract

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.

Cloning and characterization of farnesyl pyrophosphate synthase from the highly branched isoprenoid producing diatom Rhizosolenia setigera

“…The higher K m values of RsFPPS for GPP compared to DMAPP as the allylic substrate were similar to those reported for FPPS of the trematode Schistosoma mansoni 36 and FDS-2 from the sagebrush Artemisia tridentata 23 that exhibited preference for DMAPP over GPP. Decreased enzyme activity observed at the highest concentrations of IPP used (200 μM) in the enzyme assays ( Fig.…”

Physiologic Activity of Bisphosphonates – Recent Advances

“…Furthermore, malaria, which is a serious life-threatening infection caused by five different species of protozoa of the genus Plasmodium, is a huge Protozoan farnesyl pyrophosphate synthase (FPPS) is also a valuable target in the search for drugs against protozoa infections, and consequently, bisphosphonates were quite intensively studied here. The initial efforts had been concentrated on screening the influence of various series of these compounds against groups of parasites, such as Leishmania, [154,155] Plasmodium, [46,154] Trypanosoma, [154,156,157] Toxoplasma, [54,154,158] Schistosoma [159] and Cryptosporidium [160]. Thus, intensive screening of large libraries of structurally diverse bisphosphonates resulted in selection of the most effective structures and determination of the molecular mechanisms of their activities.…”

Natural Products as Leads in Schistosome Drug Discovery

“…Now that the complete genome sequences of S. mansoni [ 75 ] and S. japonicum [ 76 ] have been elucidated, genomic and proteomic approaches can be used to identify potential targets for drug design. In recent years, several interesting drug targets have been proposed, including enzymes that play an important role in the biochemical pathways of schistosomes [ 77 , 78 , 79 , 80 , 81 ]. Tanshinones, a group of abietane diterpenes isolated form Salvia miltiorrhiza and originally considered for the prevention and treatment of cardiovascular and cerebrovascular diseases [ 82 , 83 ], have been shown to inhibit S. mansoni thioredoxin glutathione reductase ( Sm TGR).…”