Terpenes Arrest Parasite Development and Inhibit Biosynthesis of Isoprenoids inPlasmodium falciparum

Abstract

Development of new drugs is one of the strategies for malaria control. The biosynthesis of several isoprenoids in Plasmodium falciparum was recently described. Interestingly, some intermediates and final products biosynthesized by this pathway in mammals differ from those biosynthesized in P. falciparum. These facts prompted us to evaluate various terpenes, molecules with a similar chemical structure to the intermediates of the isoprenoids pathway, as potential antimalarial drugs. Different terpenes and S-farnesylthiosalicylic acid were tested on cultures of the intraerythrocytic stages of P. falciparum, and the 50% inhibitory concentrations for each one were found: farnesol, 64 M; nerolidol, 760 nM; limonene, 1.22 mM; linalool, 0.28 mM; and S-farnesylthiosalicylic acid, 14 M. All the terpenes tested inhibited dolichol biosynthesis in the trophozoite and schizont stages when [1-(n)-3 H]farnesyl pyrophosphate triammonium salt ([ 3 H]FPP) was used as precursor. Farnesol, nerolidol, and linalool showed stronger inhibitory activity on the biosynthesis of the isoprenic side chain of the benzoquinone ring of ubiquinones in the schizont stage. Treatment of schizont stages with S-farnesylthiosalicylic acid led to a decrease in intensity of the band corresponding a p21 ras protein. The inhibitory effect of terpenes and S-farnesylthiosalicylic acid on the biosynthesis of both dolichol and the isoprenic side chain of ubiquinones and the isoprenylation of proteins in the intraerythrocytic stages of P. falciparum appears to be specific, because overall protein biosynthesis was not affected. Combinations of some terpenes or S-farnesylthiosalicylic acid tested in this work with other antimalarial drugs, like fosmidomycin, could be a new strategy for the treatment of malaria.

Antileishmanial Activity of the Terpene Nerolidol

“…This was confirmed by the lack of dolichol and ergosterol biosynthesis inhibition when parasites were treated with nerolidol and labeled with [1(n)-3 H]FPP. In contrast, nerolidol's inhibitory activity on the synthesis of dolichol and ubiquinone in P. falciparum was evident when [1(n)-3 H]FPP was used as a precursor, leading to the suggestion that nerolidol could act in this system by inhibiting the elongation of isoprene chains (33). Our observations in Leishmania suggest that more than one mechanism could be responsible for the antiparasitic activity of nerolidol.…”

“…This drug also hinders Plasmodium falciparum growth in vitro (23) by inhibiting the synthesis of ubiquinone and dolichol (10,33). Dolichols composed of 11 to 13 isoprene units had been previously characterized in Trypanosoma brucei, Trypanosoma cruzi, and Crithidia fasciculata (24,29,31), but the structure of these molecules had not been described for Leishmania species.…”

Isoprenoid Biosynthesis in Plasmodium falciparum

“…Supplementation of the medium with geranylgeraniol also rescues protein mislocalization and the organelle disruption effects of fosmidomycin treatment (39). Treatment with high concentrations of fosmidomycin is not completely rescued by prenyl alcohol supplementation, perhaps due to the toxicity of these compounds at high concentrations (40).…”

Use of Radioactive Precursors for Biochemical Characterization the Biosynthesis of Isoprenoids in Intraerythrocytic Stages of Plasmodium falciparum

“…Non-infected red blood cells showed no incorporation of radioactivity under these conditions. The isoprenylated proteins were later identified as members of the Ras and Rab protein family (Rodrigues Goulart et al, 2004). Moura et al (2001) and Rodrigues Goulart et al (2004) showed that terpenes can inhibit protein isoprenylation in P. falciparum.…”

“…The isoprenylated proteins were later identified as members of the Ras and Rab protein family (Rodrigues Goulart et al, 2004). Moura et al (2001) and Rodrigues Goulart et al (2004) showed that terpenes can inhibit protein isoprenylation in P. falciparum. The process of protein prenylation is a very attractive target for the development of new drugs for cancer and parasites (Docampo & Moreno 2001;Stresing et al, 2007).…”