Abstract
A fact which favors the increase in morbidity and mortality of malaria cases in the world is the resistance to chemotherapeutic agents that the parasite presents. Therefore, it is necessary to identify new potential targets specific to the parasite in order to be able to perform a rational planning. One target for the evaluation of potential antimalarial compounds is isoprenoid synthesis, which occurs via the 2-C-methyl-d -erythritol-4-phosphate pathway in Plasmodium falciparum. Several intermediaries and final products of this pathway were identified in the parasite and lead us to the conclusion that it is different from the vertebrate host. In this chapter, we describe the effect of some monoterpenes and sesquiterpenes on Plasmodium falciparum and Plasmodium berghei as potential antimalarial drugs.
Keywords
- terpenes
- malaria
- Plasmodium falciparum
- Plasmodium berghei
- isoprenoid
1. Introduction
Malaria is one of the major threats to human health, affecting an estimated number of 216 million peoples in 2016 all over the world, leading to 445,000 deaths, mainly in the African continent [1]. The human malaria is caused by six different species of the genus
The cycle begins with the injection of infective sporozoites of salivary glands of
In the bloodstream, the merosomes are then disrupted liberating the merozoites, each merozoite infecting a single red blood cell (RBC). The process of invasion is complex, relying on diverse cell machineries, which permit the parasite to attach, reorientate, and invade, forming the parasitophorous vacuole [6]. Once in the erythrocyte, the parasite starts its asexual division, passing through different stages. The early trophozoite, called “ring stage”, starts to develop, enlarging to a mature trophozoite that has a high metabolic index. In the late stage, multiple nuclear divisions are triggered without cytokinesis, forming schizonts. Each schizont holds an average of 32 merozoites (10 merozoites in average for
Within the red blood cells, the parasite can follow another path of development, differentiating into gametocytes. During a blood meal in an infected individual, the
Although
The resistance to antimalarial drugs is due to the indiscriminate use of the drugs and its incorrect use in treatment of malaria cases, such as wrong dosage, drug quality problems, erroneous diagnosis, not sticking to treatment, and others. These are characterized as treatment failure but can lead to a strong selective pressure in parasites, resulting in drug resistance. In recent years, with the emergence of artemisinin derivatives, resistance has allowed the number of cases to grow fast, especially in East Asia. Artemisinin, a sesquiterpene lactone, and its derivatives were adopted in the early 2000s as a first-line treatment in combined therapy for
The increasing resistance of the parasite to practically all current medications, such as artemisinin in five countries in Asia, Southeast Asia and probably South America [1], calls for the use of combination drug therapy, as well as for the identification of new targets [12, 13]. Targets targeting the parasite for the development of new therapies for the treatment of malaria encompass both cellular functions, such as detoxification of heme or ferriprotoporphyrin IX (Fe (III) PPIX), and folate metabolism, already explored for drugs established as antimalarial, as well as other metabolic pathways, such as fatty acid synthesis, and isoprenoid biosynthesis, both of which are found in the apicoplast [14].
The apicoplast, an organelle originating from a secondary endosymbiotic origin of red algae, has lost its photosynthetic function in the course of evolution [15], and speculations have demonstrated its importance in the formation of essential components incorporated into the membrane of the parasitophorous vacuole [16]. Recently, it has been shown that isoprenoid biosynthesis is not only essential for the parasite but, in fact, is the only function of the apicoplast during blood stage growth [17] and sexual forms [18]. Parasites that lacked apicoplast can be chemically rescued by addition of isopentenyl pyrophosphate (IPP) to the growth media [17].
2. Isoprenoids in Plasmodium spp
All isoprenoids are derived from a common precursor, IPP and its dimethylallyl pyrophosphate isomer (DMAPP) [19] (Figure 2). The identification and characterization of farnesyl pyrophosphate (FPP) in
For several decades, the mevalonate pathway, present in animals and plants, was considered the only route for synthesis of the isoprene units in isoprenoid biosynthesis. The existence of a second pathway for the biosynthesis of isoprene units was discovered in 1988 by Flesch and Rohmer when they were studying the hopanoids biosynthesis (pentacyclic triterpenic steroids) in bacteria [31]. Originally called the Rohmer’s pathway or mevalonate-independent pathway, its name was changed after the identification of the first step in the pathway (pyruvate/glyceraldehyde-3-phosphate GAP pathway) or the first intermediate, 1-deoxy-
Fosmidomycin is a natural product antibiotic with activity against a number of important pathogens (Figure 2). It is a phosphoric acid that is a substrate mimic and direct inhibitor of the first dedicated MEP pathway enzyme, in which DXP is converted to MEP by DXR (also called IspC) [35, 36]. The use of fosmidomycin as a single-drug treatment for
The first evidence for the study of isoprenoid biosynthesis in
The enzymes are important tool for study the parasite physiology and an important target for antimalarial drugs, due to its specificity. The essential step in all isoprenoids biosynthesis is the elongation of the isoprene chain by enzymes called prenyltransferases. These enzymes are classified according to the chain length of the final product and the stereochemistry of the double bond formed by condensations [47]. The most studied of these prenyltransferases has been FPPS and GGPPS in
Risedronate, a bisphosphonate containing nitrogen (N-BP), showed potent activity against the blood phases of
Many studies of novel antimalarial drugs have been performed using enzymes as the primary target of action [58, 59, 60], although in isoprenoid biosynthesis of
Since it was shown that the MEP pathway provides IPP precursors for the biosynthesis of higher isoprenic compounds, one of the strategies to identify secondary products of the MEP pathway was the metabolic labeling using a radioactive precursor and a posterior analysis by an appropriate method. In this context, it was identified in
Different types of terpenes that exert antifungal, antibacterial, and antimalarial activity can be easily found in literature [19, 64, 65]. However, not all authors described a clear explanation about their mechanism of action. Recently, Silva et al. [66] listed 114 terpenes and their semi-synthetic derivate with antimalarial activity, but only three have their mechanism of action elucidated. For several years, studies have been made of the large diversity of prenylated compounds biosynthesized by
It is known that IPP, FPP, and GGPP are substrates of the enzymes prenyltransferases involved in the biosynthesis of dolichol, the isoprenic side chain of ubiquinones, and the isoprenic chains attached to proteins, among other plasmodia prenylated compounds [68]. In order to determine if different drugs produce biosynthesis inhibitory effects on specific isoprenic compounds, treated cultures (using drugs concentration under the IC50 value), or untreated cultures can be radiolabeled by isoprenic precursors such as [1-(
Prenylated proteins are post-translational modified by farnesyl transferase and geranylgeranyl transferase by attaching isoprenic chains to C-terminal cysteine groups. Protein prenylation had already been characterized in several parasites such as
Anti-p21
Carotenoids, dolichol, and coenzyme Q are examples of prenylated compounds biosynthesized by
As we have seen, some MEP pathway and isoprenoid pathway inhibitors show good antimalarial activity and produce important metabolic alterations in
Due to the terpenes effectiveness to inhibit the
On the other hand, some metabolites derived from limonene, such as perillyl alcohol, have also been shown to be effective against the severe conditions development caused by
Furthermore, plant extracts that contain several terpenes have also been tested on experimental models. The antimalarial activity of ethanolic bark extract of
Limonoids isolated from the residual seed biomass from
In other studies, methanol extracts of
Some others triterpenes isolated from the African medicinal plant,
3. Conclusion
Acknowledgments
This work was supported by grants from Brazilian Agencies CNPq and FAPESP (Brazil). H.B.G., R.A.C.S., A.A.M.R., I.B.V., and G.C.F.L. are fellowships from FAPESP.
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