title: In vitro and in vivo antiplasmodial activities of risedronate and its interference with protein prenylation in Plasmodium falciparum.
abstract: The increasing resistance of malarial parasites to almost all available drugs calls for the identification of new compounds and the detection of novel targets. Here, we establish the antimalarial activities of risedronate, one of the most potent bisphosphonates clinically used to treat bone resorption diseases, against blood stages of Plasmodium falciparum (50% inhibitory concentration [IC50] of 20.3±1.0 μM). We also suggest a mechanism of action for risedronate against the intraerythrocytic stage of P. falciparum and show that protein prenylation seems to be modulated directly by this drug. Risedronate inhibits the transfer of the farnesyl pyrophosphate group to parasite proteins, an effect not observed for the transfer of geranylgeranyl pyrophosphate. Our in vivo experiments further demonstrate that risedronate leads to an 88.9% inhibition of the rodent parasite Plasmodium berghei in mice on the seventh day of treatment; however, risedronate treatment did not result in a general increase of survival rates.
authors.affiliation: Department of Parasitology, Institute of Biomedical Sciences, University of São Paulo, Av. Professor Lineu Prestes 1374, CEP 05508-000, São Paulo, SP, Brazil.
authors.forename: Fabiana Morandi
authors.initials: FM
authors.lastname: Jordão
authors.forename: Alexandre Yukio
authors.initials: AY
authors.lastname: Saito
authors.forename: Danilo Ciccone
authors.initials: DC
authors.lastname: Miguel
authors.forename: Valnice
authors.initials: V
authors.lastname: de Jesus Peres
authors.forename: Emília Akemi
authors.initials: EA
authors.lastname: Kimura
authors.forename: Alejandro Miguel
authors.initials: AM
authors.lastname: Katzin
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000627:therapeutic use*; D002855:Chromatography, Thin Layer; D012968:Etidronic Acid / Q000031:analogs & derivatives* / Q000627:therapeutic use; D020128:Inhibitory Concentration 50; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000378:metabolism* / Q000472:pathogenicity; D017368:Protein Prenylation / Q000187:drug effects; D000068296:Risedronic Acid; D013729:Terpenes / Q000378:metabolism
chemical_list: D000962:Antimalarials; D013729:Terpenes; D000068296:Risedronic Acid; D012968:Etidronic Acid