Open AccessIn VitroandIn VivoAntiplasmodial Activities of Risedronate and Its Interference with Protein Prenylation in Plasmodium falciparum
Author(s) -
Fabiana Morandi Jordão,
Alexandre Yukio Saito,
Danilo C. Miguel,
Valnice de Jesus Peres,
Emı́lia A. Kimura,
Alejandro M. Katzin
Publication year - 2011
Publication title -
antimicrobial agents and chemotherapy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.07
H-Index - 259
eISSN - 1070-6283
pISSN - 0066-4804
DOI - 10.1128/aac.01820-10
Subject(s) - plasmodium falciparum , prenylation , in vivo , pharmacology , plasmodium berghei , biology , chemistry , malaria , immunology , biochemistry , microbiology and biotechnology , enzyme
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.