Terpenes arrest parasite development and inhibit biosynthesis of isoprenoids in Plasmodium falciparum
Development of new drugs is one of the strategies for malaria control. The biosynthesis of several isoprenoids in Plasmodiumfalciparum was recently described. Interestingly, some intermediates and final products biosynthesized by this pathway in mammals differ from those biosynthesized in P. falcipa...
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todo:paper_00664804_v48_n7_p2502_Goulart2023-10-03T14:53:05Z Terpenes arrest parasite development and inhibit biosynthesis of isoprenoids in Plasmodium falciparum Goulart, H.R. Kimura, E.A. Peres, V.J. Couto, A.S. Duarte, F.A.A. Katzin, A.M. antimalarial agent farnesol farnesylthiosalicylic acid fosmidomycin isoprenoid limonene linalool nerolidol terpene derivative antimalarial activity article biosynthesis concentration response controlled study developmental stage malaria malaria control minimum inhibitory concentration nonhuman parasite development Plasmodium falciparum priority journal protein synthesis schizont steroidogenesis trophozoite Animals Chromatography, High Pressure Liquid Chromatography, Thin Layer Depression, Chemical Dolichol Electrophoresis, Polyacrylamide Gel Erythrocytes Farnesol Lipid Metabolism Malaria, Falciparum Plasmodium falciparum Precipitin Tests Salicylic Acids Terpenes Ubiquinone Development of new drugs is one of the strategies for malaria control. The biosynthesis of several isoprenoids in Plasmodiumfalciparum 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 μM; nerolidol, 760 nM; limonene, 1.22 mM; linalool, 0.28 mM; and S-farnesylthiosalicylic acid, 14 μM. All the terpenes tested inhibited dolichol biosynthesis in the trophozoite and schizont stages when [1-(n)- 3H]farnesyl pyrophosphate triammonium salt ([3H]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 p21ras 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. JOUR info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by/2.5/ar http://hdl.handle.net/20.500.12110/paper_00664804_v48_n7_p2502_Goulart |
| institution |
Universidad de Buenos Aires |
| institution_str |
I-28 |
| repository_str |
R-134 |
| collection |
Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) |
| topic |
antimalarial agent farnesol farnesylthiosalicylic acid fosmidomycin isoprenoid limonene linalool nerolidol terpene derivative antimalarial activity article biosynthesis concentration response controlled study developmental stage malaria malaria control minimum inhibitory concentration nonhuman parasite development Plasmodium falciparum priority journal protein synthesis schizont steroidogenesis trophozoite Animals Chromatography, High Pressure Liquid Chromatography, Thin Layer Depression, Chemical Dolichol Electrophoresis, Polyacrylamide Gel Erythrocytes Farnesol Lipid Metabolism Malaria, Falciparum Plasmodium falciparum Precipitin Tests Salicylic Acids Terpenes Ubiquinone |
| spellingShingle |
antimalarial agent farnesol farnesylthiosalicylic acid fosmidomycin isoprenoid limonene linalool nerolidol terpene derivative antimalarial activity article biosynthesis concentration response controlled study developmental stage malaria malaria control minimum inhibitory concentration nonhuman parasite development Plasmodium falciparum priority journal protein synthesis schizont steroidogenesis trophozoite Animals Chromatography, High Pressure Liquid Chromatography, Thin Layer Depression, Chemical Dolichol Electrophoresis, Polyacrylamide Gel Erythrocytes Farnesol Lipid Metabolism Malaria, Falciparum Plasmodium falciparum Precipitin Tests Salicylic Acids Terpenes Ubiquinone Goulart, H.R. Kimura, E.A. Peres, V.J. Couto, A.S. Duarte, F.A.A. Katzin, A.M. Terpenes arrest parasite development and inhibit biosynthesis of isoprenoids in Plasmodium falciparum |
| topic_facet |
antimalarial agent farnesol farnesylthiosalicylic acid fosmidomycin isoprenoid limonene linalool nerolidol terpene derivative antimalarial activity article biosynthesis concentration response controlled study developmental stage malaria malaria control minimum inhibitory concentration nonhuman parasite development Plasmodium falciparum priority journal protein synthesis schizont steroidogenesis trophozoite Animals Chromatography, High Pressure Liquid Chromatography, Thin Layer Depression, Chemical Dolichol Electrophoresis, Polyacrylamide Gel Erythrocytes Farnesol Lipid Metabolism Malaria, Falciparum Plasmodium falciparum Precipitin Tests Salicylic Acids Terpenes Ubiquinone |
| description |
Development of new drugs is one of the strategies for malaria control. The biosynthesis of several isoprenoids in Plasmodiumfalciparum 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 μM; nerolidol, 760 nM; limonene, 1.22 mM; linalool, 0.28 mM; and S-farnesylthiosalicylic acid, 14 μM. All the terpenes tested inhibited dolichol biosynthesis in the trophozoite and schizont stages when [1-(n)- 3H]farnesyl pyrophosphate triammonium salt ([3H]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 p21ras 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. |
| format |
JOUR |
| author |
Goulart, H.R. Kimura, E.A. Peres, V.J. Couto, A.S. Duarte, F.A.A. Katzin, A.M. |
| author_facet |
Goulart, H.R. Kimura, E.A. Peres, V.J. Couto, A.S. Duarte, F.A.A. Katzin, A.M. |
| author_sort |
Goulart, H.R. |
| title |
Terpenes arrest parasite development and inhibit biosynthesis of isoprenoids in Plasmodium falciparum |
| title_short |
Terpenes arrest parasite development and inhibit biosynthesis of isoprenoids in Plasmodium falciparum |
| title_full |
Terpenes arrest parasite development and inhibit biosynthesis of isoprenoids in Plasmodium falciparum |
| title_fullStr |
Terpenes arrest parasite development and inhibit biosynthesis of isoprenoids in Plasmodium falciparum |
| title_full_unstemmed |
Terpenes arrest parasite development and inhibit biosynthesis of isoprenoids in Plasmodium falciparum |
| title_sort |
terpenes arrest parasite development and inhibit biosynthesis of isoprenoids in plasmodium falciparum |
| url |
http://hdl.handle.net/20.500.12110/paper_00664804_v48_n7_p2502_Goulart |
| work_keys_str_mv |
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