Antiparasitic activity of risedronate in a murine model of acute Chagas’ disease

Garzoni, Luciana Ribeiro; Waghabi, Mariana Caldas; Baptista, Marcos M; Castro, Solange L. de; Meirelles, Maria de Nazareth Leal de; Britto, Constança; Docampo, Roberto; Oldfield, Eric; Urbina, Julio A.

doi:10.1016/j.ijantimicag.2003.07.019

Cited by 88 publications

(70 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Another class of drugs in clinical use are the nitrogen-containing bisphosphonates (N-BPs) that inhibit FPPS, used to treat disorders characterized by bone resorption such as osteoporosis, Paget disease, or multiple myeloma (10). Further targets for drug development presently being explored are the protein prenyltransferases for the treatment of cancer (11) or FPPS from protozoan parasites for the treatment of malaria, Leishmaniasis, and Chagas disease (12,13).…”

mentioning

confidence: 99%

The Crystal Structure of Human Geranylgeranyl Pyrophosphate Synthase Reveals a Novel Hexameric Arrangement and Inhibitory Product Binding

Kavanagh

Dunford

Bunkóczi

et al. 2006

Journal of Biological Chemistry

146

201

View full text Add to dashboard Cite

Modification of GTPases with isoprenoid molecules derived from geranylgeranyl pyrophosphate or farnesyl pyrophosphate is an essential requisite for cellular signaling pathways. The synthesis of these isoprenoids proceeds in mammals through the mevalonate pathway, and the final steps in the synthesis are catalyzed by the related enzymes farnesyl pyrophosphate synthase and geranylgeranyl pyrophosphate synthase. Both enzymes play crucial roles in cell survival, and inhibition of farnesyl pyrophosphate synthase by nitrogen-containing bisphosphonates is an established concept in the treatment of bone disorders such as osteoporosis or certain forms of cancer in bone. Here we report the crystal structure of human geranylgeranyl pyrophosphate synthase, the first mammalian ortholog to have its x-ray structure determined. It reveals that three dimers join together to form a propeller-bladed hexameric molecule with a mass of ϳ200 kDa. Structure-based sequence alignments predict this quaternary structure to be restricted to mammalian and insect orthologs, whereas fungal, bacterial, archaeal, and plant forms exhibit the dimeric organization also observed in farnesyl pyrophosphate synthase. Geranylgeranyl pyrophosphate derived from heterologous bacterial expression is tightly bound in a cavity distinct from the chain elongation site described for farnesyl pyrophosphate synthase. The structure most likely represents an inhibitory complex, which is further corroborated by steadystate kinetics, suggesting a possible feedback mechanism for regulating enzyme activity. Structural comparisons between members of this enzyme class give deeper insights into conserved features important for catalysis.

show abstract

mentioning

confidence: 99%

The Crystal Structure of Human Geranylgeranyl Pyrophosphate Synthase Reveals a Novel Hexameric Arrangement and Inhibitory Product Binding

Kavanagh

Dunford

Bunkóczi

et al. 2006

Journal of Biological Chemistry

146

201

View full text Add to dashboard Cite

show abstract

“…Enzymes studied so far involved in the synthesis of sterols (2), farnesyl diphosphate (3), and protein prenylation (4) have been reported to be good drug targets against this parasite. The farnesyl-diphosphate synthase, for example, has been demonstrated to be the target of bisphosphonates that have activity in vitro and in vivo against T. cruzi (3,(5)(6)(7)(8)(9).…”

mentioning

confidence: 99%

A Solanesyl-diphosphate Synthase Localizes in Glycosomes of Trypanosoma cruzi

Ferella

Montalvetti

Rohloff

et al. 2006

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

We report the cloning of a Trypanosoma cruzi gene encoding a solanesyl-diphosphate synthase, TcSPPS. The amino acid sequence (molecular mass ϳ 39 kDa) is homologous to polyprenyl-diphosphate synthases from different organisms, showing the seven conserved motifs and the typical hydrophobic profile. TcSPPS preferred geranylgeranyl diphosphate as the allylic substrate. The final product, as determined by TLC, had nine isoprene units. This suggests that the parasite synthesizes mainly ubiquinone-9 (UQ-9), as described for Trypanosoma brucei and Leishmania major. In fact, that was the length of the ubiquinone extracted from epimastigotes, as determined by high-performance liquid chromatography. Expression of TcSPPS was able to complement an Escherichia coli ispB mutant. A punctuated pattern in the cytoplasm of the parasite was detected by immunofluorescence analysis with a specific polyclonal antibody against TcSPPS. An overlapping fluorescence pattern was observed using an antibody directed against the glycosomal marker pyruvate phosphate dikinase, suggesting that this step of the isoprenoid biosynthetic pathway is located in the glycosomes. Co-localization in glycosomes was confirmed by immunogold electron microscopy and subcellular fractionation. Because UQ has a central role in energy production and in reoxidation of reduction equivalents, TcSPPS is promising as a new chemotherapeutic target.

show abstract

“…The first report of this activity in animal models demonstrated that risedronate could reduce parasitemia with reductions in mortality, but no complete parasitological cures were achieved 126 . In another study, a significant reduction in mortality was observed when CD-1 mice were treated with risedronate, but myocardial pathology and ventricular dilatation was unchanged in comparison with control.…”

Section: Inhibitors Of Pyrophosphate Metabolismmentioning

confidence: 99%

Current and Future Chemotherapy for Chagas Disease

Gaspar¹,

Moraes²,

Freitas‐Junior³

et al. 2015

CMC

View full text Add to dashboard Cite

American trypanosomiasis, commonly called Chagas disease, is one of the most neglected illnesses in the world and remains one of the most prevalent chronic infectious diseases of Latin America with thousands of new cases every year. The only treatments available have been introduced five decades ago. They have serious, undesirable side effects and disputed benefits in the chronic stage of the disease -a characteristic and debilitating cardiomyopathy and/or megavisceras. Several laboratories have therefore focused their efforts in finding better drugs. Although recent years have brought new clinical trials, these are few and lack diversity in terms of drug mechanism of action, thus resulting in a weak drug discovery pipeline. This fragility has been recently exposed by the failure of two candidates, posaconazole and E1224, to sterilely cure patients in phase 2 clinical trials. Such setbacks highlight the need for continuous, novel and high quality drug discovery and development efforts to discover better and safer treatments.In this article we will review past and current findings on drug discovery for Trypanosoma cruzi made by academic research groups, industry and other research organizations over the last half century. 2We will also analyze the current research landscape that is now better placed than ever to deliver alternative treatments for Chagas disease in the near future.

show abstract

Antiparasitic activity of risedronate in a murine model of acute Chagas’ disease

Cited by 88 publications

References 21 publications

The Crystal Structure of Human Geranylgeranyl Pyrophosphate Synthase Reveals a Novel Hexameric Arrangement and Inhibitory Product Binding

The Crystal Structure of Human Geranylgeranyl Pyrophosphate Synthase Reveals a Novel Hexameric Arrangement and Inhibitory Product Binding

A Solanesyl-diphosphate Synthase Localizes in Glycosomes of Trypanosoma cruzi

Current and Future Chemotherapy for Chagas Disease

Contact Info

Product

Resources

About