Last Updated: 13/10/2025
Biosynthesis of isoprenoids in Plasmodium falciparum: evaluation of possible targets for obtaining new antimalarial drugs
Objectives
The project focuses on identifying new targets for antimalarial drug development by studying the biosynthesis of isoprenoids in Plasmodium falciparum, particularly during its intraerythrocytic stages. It aims to confirm the presence of cytokinins and ubiquinones, explore inhibitors of key enzymes in the shikimate pathway, and evaluate synthetic terpenes for their potential antimalarial effects, ultimately seeking innovative therapeutic strategies against malaria.
One fact that favors the increase in morbidity and mortality from malaria worldwide is the resistance to chemotherapeutic agents that the parasite presents. Therefore, it is necessary to identify new potential specific targets in the parasite in order to be able to execute a rational planning. The present project aims to complement the studies that have been developed in the investigators’ laboratory for over 35 years on the biosynthesis of isoprenoids in the intraerythrocytic stages of Plasmodium falciparum. All isoprenoids derive from a common precursor, isopentenyl pyrophosphate, and its isomer dimethylallyl pyrophosphate, with prenyl synthase enzymes being responsible for catalyzing the sequential condensation of isoprene units. Several intermediates and final products of this pathway were identified in the parasite by the research team, which led them to conclude that it is different from that of the vertebrate host. Therefore, the researchers can identify potential targets for evaluating antimalarial drugs.
In this line of research, the investigators continue this project, identifying other products derived from the biosynthesis of isoprenoids in the intraerythrocytic forms of P. falciparum, the cytokinins. Cytokinins are substances chemically related to the same biosynthetic pathways as terpenoids, carotenoids, gibberellins, and abscisic acid. All these substances are derived from dimethylallyl isoprene pyrophosphate, with the 2C-methyl-D-erythritol-4-phosphate (MEP) pathway as a precursor source. In the investigators’ laboratory, different cytokinins were identified in the intraerythrocytic stages of P. falciparum through metabolic labeling, and they determined that the cytokinins isopentenyladenosine and trans-zeatin are capable of stimulating the growth of the parasite. To confirm the presence of these cytokinins in the intraerythrocytic stages of P. falciparum, the team must identify them by mass spectrometry (LC-MS) and quantify the growth of the parasites in their presence.
The ubiquinones (UQ 8-9), described in P. falciparum, have a structure composed of an isoprene chain from the MEP pathway and an aromatic group from the shikimate pathway, both of which are absent in mammalian cells. In the investigators’ laboratory, the isoprene chains and the shikimate and chorismate precursors of the aromatic ring of ubiquinones were identified by metabolic labeling. The presence of these intermediates must be confirmed by mass spectrometry in the intraerythrocytic stages of P. falciparum. Once the shikimate biosynthesis pathway is confirmed, different inhibitors derived from 5-caffeoylquinic acid will be evaluated. Inhibition of specific enzymes of the shikimate pathway, as well as of the enzyme 4-hydroxybenzoate polyprenyltransferase, may lead to a deficiency in the biosynthesis of prenylquinones essential for the respiratory chain of the parasite.
In the investigators’ laboratory, several enzymes related to isoprenoid biosynthesis have been identified, and the research team recently identified a prenol kinase that is capable of phosphorylating 20C polyprenols and intends to evaluate different inhibitors of this enzyme. The identification and characterization of inhibitors of prenol kinase, involved in the utilization of exogenous and endogenous prenols by the parasite, may reveal new opportunities for the development of combination therapies. Synthetic terpenes, such as geranylgeranylacetone (GGA), have antimalarial potential by interfering with the parasite’s prenylation processes and the utilization of exogenous isoprenoids. The exploration of these compounds may lead to the development of new classes of antimalarial drugs with innovative modes of action. Furthermore, PolK appears to be involved in the regulation of carbon metabolism and glycolysis, another aspect that the present proposal aims to evaluate.
Apr 2025 — Mar 2027
