Title: In Vitro and In Vivo Antiplasmodial Activities of Risedronate and Its Interference with Protein Prenylation in Plasmodium falciparum
Author: Jordao, F. M.; Saito, A. Y.; Miguel, D. C.; De Jesus Peres, V.; Kimura, E. A.; Katzin, A. M.
Is part of: Antimicrobial Agents and Chemotherapy (Print), v. 55, p. 2026 - 2031
Citation: Jordao, F. M.; Saito, A. Y.; Miguel, D. C.; De Jesus Peres, V.; Kimura, E. A.; Katzin, A. M.; In Vitro and In Vivo Antiplasmodial Activities of Risedronate and Its Interference with Protein Prenylation in Plasmodium falciparum. Antimicrobial Agents and Chemotherapy (Print), v.55, p. 2026-2031, 2011
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 [IC(50)] of 20.3 +/- 1.0 mu M). 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.
Funding: This work was supported by grants from CNPq and FAPESP (Brazil). F.M.J. is the recipient of a postgraduate fellowship from CNPq. A.Y.S. and D.C.M. receive postgraduate fellowships from FAPESP.