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Tafere Mulaw Belete Department of Pharmacology, Faculty of Medicine and Health Sciences, Gondar University, Gondar, Ethiopia Correspondence: Tafere Mulaw Belete Tel +251 918045943Email [email protected] Abstract: Malaria is a major global health problem causing significant mortality and morbidity every year Rate.Treatment options are scarce and greatly challenged by the emergence of resistant parasite strains, which pose a significant obstacle to malaria control.To prevent potential public health emergencies, novel antimalarial drugs with single-dose therapy, broad therapeutic potential, and novel mechanisms of action are urgently needed.Antimalarial drug development can follow a variety of approaches, ranging from the modification of existing drugs to the design of novel drugs targeting new targets.Modern advances in parasite biology and the availability of different genomic technologies provide a wide range of new targets for the development of new therapeutics.Several promising targets for drug intervention have been revealed in recent years.Therefore, this review focuses on the latest scientific and technological advances in the discovery and development of novel antimalarial drugs.The most interesting antimalarial target proteins studied so far include proteases, protein kinases, plasmodium sugar transporter inhibitors, aquaporin 3 inhibitors, choline transport inhibitors, dihydroorotate dehydrogenase inhibitors, pentadiene biosynthesis inhibitor, farnesyltransferase inhibitor and enzymes involved in lipid metabolism and DNA replication.This review summarizes new molecular targets for antimalarial drug development and their inhibitors.Key words: drug resistance, new targets, antimalarial drugs, mode of action, malaria parasite
Malaria is a devastating parasitic infectious disease, especially in sub-Saharan Africa, parts of Asia and South America.Despite several efforts, today it is one of the leading causes of morbidity and mortality mainly in pregnant women and children.According to the World Health Organization (WHO) 2018 report, there were 228 million malaria cases and 405,000 deaths globally.Almost half of the world’s population is at risk of malaria, with the majority of cases (93%) and deaths (94%) occurring in Africa.About 125 million pregnant women are at risk of malaria each year, and 272,000 children under the age of 5 die from malaria.1 Malaria is also a cause of poverty and a major obstacle to economic development, mainly in Africa.2 The five identified species of Plasmodium that cause malaria in humans are P. vivax, P. knowlesi, P. ovale, P. malaria and P. falciparum.Of these, Plasmodium falciparum is the most lethal and prevalent species of Plasmodium.3
In the absence of an effective vaccine, the therapeutic use of antimalarial drugs remains the only way to manage and prevent malaria disease.Several studies have shown that the efficacy of most antimalarial drugs is compromised by emergencies in drug-resistant Plasmodium spp.4 Drug resistance has been reported with almost all available antimalarial drugs, reinforcing the development of new antimalarial drugs against existing validated targets and the search for The gametophytic stage of transmission can also act on asexual proliferation within erythrocytes, especially in resistant parasite species.6 Several enzymes, ion channels, transporters, interacting molecules Red blood cell (RBC) invasion, and molecules responsible for parasite oxidative stress, lipid metabolism, and hemoglobin degradation are key to the development of new antimalarial drugs against rapidly mutating malaria Promising new targets for protozoa.7
The potential of new antimalarial drugs is judged by several requirements: a new mode of action, no cross-resistance to current antimalarial drugs, single-dose treatment, efficacy against both the asexual blood stage and the gametocytes responsible for transmission.In addition, new antimalarial drugs should have efficacy in preventing infection (chemoprotectants) and clearing the liver of P. vivax hypnotics (anti-relapse agents).8
Traditional drug discovery follows a number of approaches to identifying a new antimalarial drug to fight malaria.These are optimizing current drug regimens and formulations, modifying existing antimalarial drugs, screening natural products, isolating resistance-reversing agents, utilizing combination chemotherapy approaches, and developing drugs for other uses.8,9
In addition to traditional drug discovery methods used to identify novel antimalarial drugs, knowledge of the Plasmodium cell biology and genome has been shown to be a powerful tool for uncovering drug resistance mechanisms, and has the potential to design drugs with high antimalarial and antimalarial activity. Great potential for new drugs.Fighting malaria’s transmission interruption potential once and for all.10 Genetic screening of Plasmodium falciparum identified 2680 genes important for asexual blood-phase growth, thereby identifying key cellular processes that are critical for developing new drugs.10,11 New drugs should: (i) address drug resistance, (ii) act rapidly, (iii) be safe, especially in children and pregnant women, and (iv) cure malaria in a single dose.12 The challenge is to find a drug that addresses all of these characteristics.The purpose of this review is to give an idea of new targets for the treatment of malaria parasites, which are being studied by several companies, so that readers can be informed of previous work.
Currently, most antimalarial drugs target the asexual stage of malaria infection that causes symptomatic disease.The pre-erythrocytic (liver) stage remains unattractive because no clinical symptoms are produced.Antimalarial drugs exhibit considerable phase selectivity (see Figure 1).Malaria treatment based on natural products, semi-synthetic and synthetic compounds developed since the 1940s.13 Existing antimalarial drugs fall into three broad categories: quinoline derivatives, antifolates and artemisinin derivatives.No single drug has yet been discovered or manufactured that can eradicate all species of malaria parasites.Therefore, to be effective against malaria infection, combinations of drugs are often administered simultaneously.Quinoline is the most widely used antimalarial drug for the treatment of malaria.Quinine, an alkaloid isolated from the bark of the cinchona tree, was the first antimalarial drug used to treat disease in the 17th century.From the mid-1800s to the 1940s, quinine was the standard treatment for malaria.14 In addition to toxicity, the emergence of drug-resistant strains of P. falciparum has limited the therapeutic use of quinine.However, quinine is still used to treat severe malaria, most often in combination with a second drug to shorten treatment time and minimize side effects.15,16
Figure 1 The life cycle of Plasmodium in humans.Stages and forms of parasites in which different types of antimalarial drugs act.
In 1925, German researchers discovered the first synthetic antimalarial drug, pamaquin, by modifying methylene blue.Pamaquin has limited efficacy and toxicity and cannot be used to treat malaria.But pamaquin provides lead compounds to develop better antimalarial drugs.Mepacrine (quinacrine) is another derivative of methylene blue used to treat malaria during World War II.17
Chloroquine was developed during World War II to treat malaria.Chloroquine is the drug of choice for the treatment of malaria due to its efficacy, safety and low cost.But its irrational use soon led to the emergence of chloroquine-resistant P. falciparum species.18 Primaquine is used therapeutically to treat relapsing Plasmodium vivax caused by hypnosis.Primaquine is potent gameticidal against Plasmodium falciparum.Primaquine causes hemolytic anemia in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency.This hemolysis exacerbates the need for new drugs with anti-P.Diurnal activity.19
New quinoline derivatives were synthesized, resulting in new drugs such as piperaquine and amodiaquine.After the emergence of chloroquine resistance, amodiaquine, a phenyl-substituted analog of chloroquine, showed excellent efficacy against chloroquine-resistant strains of Plasmodium falciparum.20 Pyrronadrine is a Mannich base antimalarial drug developed in China in 1970.It is effective against drug-resistant strains of P. falciparum, P. vivax, P. malaria and P. ovale.Pyronadrine is now available as ACT with artesunate, which has shown excellent efficacy against all malaria parasites.21 Mefloquine was developed in the mid-1980s and is currently recommended for chemoprevention of malaria caused by all species, including chloroquine-resistant strains.However, its use is associated with some side effects and drug resistance.22 Quinoline-derived drugs act primarily on the blood stage of the parasite, but some antimalarial drugs act on the liver stage.These drugs inhibit by forming a complex with heme in the parasite’s food vacuoles.Therefore, heme polymerization is blocked.As a result, the heme released during the breakdown of hemoglobin accumulates to toxic levels, killing the parasite with toxic waste.twenty three
Antifolates are antimalarial drugs that inhibit the synthesis of folic acid, which is essential for the synthesis of nucleotides and amino acids.Antifolates block nuclear division of Plasmodium species during the schizont phase in erythrocytes and hepatocytes.Sulfadoxine has a similar structure to para-aminobenzoic acid (PABA), a component of folic acid.They inhibit dihydrofolate synthesis by inhibiting dihydrofolate synthase, a key enzyme in nucleic acid biosynthesis.twenty four
Pyrimethamine and proguanil are schizont antimalarial drugs that act on the asexual form of Plasmodium species.These drugs inhibit the enzyme dihydrofolate reductase (DHFR), which inhibits the reduction of dihydrofolate to tetrahydrofolate, which is essential for the biosynthesis of amino acids and nucleic acids.Proguanil is a prodrug metabolized to cyclic guanidine.Proguanil was the first antifolate drug used in the treatment of malaria.The reason is that it destroys the red blood cells before the parasite invades them during their entry into the bloodstream.Also, proguanil is a safe drug.Pyrimethamine is mainly used with other fast-acting drugs.However, its use has decreased due to drug resistance.24,25
Atovaquone is the first approved antimalarial drug targeting the mitochondria of the Plasmodium parasite.Atovaquone inhibits electron transport by acting as a ubiquinone analog to block the cytochrome b portion of the cytochrome bc1 complex.When combined with proguanil, atovaquone is safe and effective for pregnant women and children.Atovaquone is effective against the sexual stage of the parasite of the host and mosquito.Thus, it inhibits the transmission of malaria from mosquitoes to humans.A fixed combination with proguanil developed under the trade name Malarone.24,26
Artemisinin was extracted from Artemisia annua in 1972.Artemisinin and its derivatives including artemether, dihydroartemisinin, artemether and artesunate have broad spectrum activity.Artemisinin inhibits all parasite stages within red blood cells, especially in the early stages of their development.It also inhibits the transmission of gametocytes from humans to mosquitoes.27 Artemisinin and its derivatives are effective against chloroquine- and mefloquine-resistant strains.They are safe, effective and fast-acting blood schizonts against all Plasmodium species.However, artemisinin did not clear the hepatic latency of the parasite.These drugs have short half-lives and poor bioavailability, leading to drug resistance, rendering them ineffective as monotherapy.Therefore, artemisinin derivatives are recommended in combination with other antimalarial drugs.28
The antimalarial effect of artemisinin may be due to the generation of free radicals that result from the cleavage of artemisinin endoperoxide bridges in parasite food vesicles, thereby inhibiting parasite calcium ATPase and proteasome.29,30 Artemether is used as monotherapy.Fast oral absorption.Bioavailability doubled when administered in the presence of food.Once in the systemic circulation, artemether is hydrolyzed to dihydroartemisinin in the gut and liver.
Artesunate is a semi-synthetic derivative due to its rapid antimalarial effect, lack of significant drug resistance and greater water solubility.Recommended as a first-line drug for severe malaria.31
Tetracyclines and macrolides are slow-acting antimalarial drugs used as adjunctive therapy to quinine in falciparum malaria.Doxycycline is also used for chemoprophylaxis in areas with high resistance.32 The current strategy used to combat antimalarial drug resistance is the therapeutic use of drug combinations.This strategy has been used in the past by using fixed combinations.WHO recommends artemisinin-based combination therapy (ACT) as the first-line treatment for uncomplicated falciparum malaria.The reason is that the combination of drugs reduces drug resistance and side effects.33
ACT contains a potent artemisinin component that quickly clears parasites, and a long-acting drug that eliminates residual parasites and reduces artemisinin resistance.The ACTs recommended by WHO are artesunate/amodiaquine, artemether/ benzfluorenol, artesunate/mefloquine, artesunate/pyrrolidine, dihydroartemisinin/piperaquine, Artesunate/sulfadoxine/pyrimethamine, artemether/piperaquine and artemisinin/piperaquine/primaquine.Chloroquine plus primaquine remains the first-line drug for the eradication of Plasmodium vivax.Quinine + tetracycline/doxycycline has a high cure rate, but it has serious side effects and is contraindicated in children and pregnant women34.
Mefloquine, atovaquone/proguanil, or doxycycline are recommended in chemoprevention regimens for travelers from non-endemic to endemic areas.35 Intermittent preventive treatment in high-risk groups is advocated, including sulfadoxine/pyrimethamine during pregnancy and amodiaquine/sulfadoxine-pyrimethamine as seasonal chemoprevention.36 Halofantrine is not suitable for therapeutic use due to its cardiotoxicity.Dapsone, mepalyline, amodiaquine, and sulfonamides were withdrawn from therapeutic use due to their side effects.36,37 Some well-known antimalarial drugs and their side effects are listed in Table 1.
Currently available antimalarial drugs are based on differences in major metabolic pathways between Plasmodium species and their hosts.The parasite’s major metabolic pathways, including heme detoxification, fatty acid synthesis, nucleic acid synthesis, fatty acid synthesis, and oxidative stress, are some of the novel sites for drug design.38,39 Although most antimalarial drugs have been used for several years, their use is currently limited due to drug resistance.According to the literature, no antimalarial drugs have been found that inhibit known drug targets.7,40 In contrast, most antimalarial drugs are discovered in animal in vivo or in vitro model studies.Therefore, the mode of action of most antimalarial drugs remains uncertain.Furthermore, the mechanisms of resistance to most antimalarial drugs are unclear.39
Malaria control requires coordinated strategies such as vector control, effective and safe antimalarial drugs, and effective vaccines.Considering the high mortality and morbidity of malaria, emergencies and the spread of drug resistance, the ineffectiveness of existing antimalarial drugs against non-erythrocyte and sexual stages, identification of new antimalarial drugs by understanding the basic metabolic pathways of malaria. Malaria medicines are crucial.parasites.To achieve this goal, drug research should target new, validated targets to isolate new lead compounds.39,41
There are several reasons for the need to identify new metabolic targets.First, with the exception of atovaquone and artemisinin-derived drugs, most antimalarial drugs are not chemically diverse, which may lead to cross-resistance.Second, due to the wide variety of putative chemotherapeutic targets, many have yet to be validated.If validated, it may yield some compounds that are effective and safe.The identification of new drug targets and the design of new compounds that act on the new targets are widely used worldwide today to address problems arising from the emergence of resistance to existing drugs.40,41 Therefore, the study of novel target protein-specific inhibitors of Plasmodium has been used for drug target identification.Since the unveiling of the P. falciparum genome, several new targets for drug intervention have emerged.These potential antimalarial drugs target key metabolite biosynthesis, membrane transport and signaling systems, and hemoglobin degradation processes.40,42
Plasmodium protease is a ubiquitous catalytic and regulatory enzyme that plays a key role in the survival of protozoan parasites and the diseases they cause.It catalyzes the hydrolysis of peptide bonds.43 The roles of proteases in malaria disease pathogenesis include cell/tissue penetration, immune evasion, activation of inflammation, erythrocyte invasion, breakdown of hemoglobin and other proteins, autophagy, and parasite development.44
Malaria proteases (glutamic aspartic acid, cysteine, metal, serine and threonine) are promising therapeutic targets because disruption of the malaria protease gene inhibits the degradation of hemoglobin and the parasite’s erythrocyte stage. development.45
The breakdown of erythrocytes and subsequent invasion of merozoites requires malaria proteases.A synthetic peptide (GlcA-Val-Leu-Gly-Lys-NHC2H5) inhibits the Plasmodium falciparum schizont cysteine protease Pf 68.It inhibits erythrocyte invasion and parasite development.This suggests that proteases play a key role in the parasite’s invasion of red blood cells.Therefore, proteases are a promising target for antimalarial drug development.46
In Plasmodium falciparum food vacuoles, several aspartic proteases (plasma proteases I, II, III, IV) and cysteine proteases (falcipain-1, falcipain-2/, falcipain-3) have been isolated, Used to degrade hemoglobin, as shown in Figure 2.
Incubation of cultured P. falciparum parasites with the protease inhibitors leupeptin and E-64 resulted in the accumulation of undegraded globin.Leupeptin inhibits cysteine and some serine proteases, but E-64 specifically inhibits cysteine proteases.47,48 After incubation of parasites with the aspartate protease inhibitor pepstatin, globin did not accumulate.Several studies have shown that cystatin inhibitors not only inhibit globin degradation, but also inhibit the early steps of hemoglobin breakdown, such as hemoglobin denaturation, heme release from globin, and heme production.49 These results suggest that cysteine proteases are required for the initial stage.Steps in the degradation of hemoglobin by Plasmodium falciparum.Both E-64 and pepstatin synergistically block P. falciparum development.However, only E-64 blocked globin hydrolysis.48,49 Several cysteine protease inhibitors, such as fluoromethyl ketone and vinyl sulfone, inhibit P. falciparum growth and hemoglobin degradation.In an animal model of malaria, fluoromethyl ketone inhibits P. vinckei protease activity and cures 80% of murine malaria infections.Therefore, protease inhibitors are promising candidates for antimalarial drugs.Subsequent work identified biologically active falcipain inhibitors, including chalcone and phenothiazine, which block parasite metabolism and development.50
Serine proteases are involved in schizont rupture and erythrocyte reinvasion during the Plasmodium falciparum life cycle.It can be blocked by several serine protease inhibitors and is the best choice since no human enzyme homolog is available.The protease inhibitor LK3 isolated from Streptomyces sp. degrades the malaria serine protease.51 Maslinic acid is a natural pentacyclic triterpenoid that inhibits the maturation of parasites from the ring stage to the schizont stage, thereby terminating the release of merozoites and their invasion.A series of potent 2-pyrimidine nitrile inhibition of falcipain-2 and falcipain-3.52 statins and inhibition of plasma proteases by allophenostatin-based inhibitors prevent hemoglobin degradation and kill parasites.Several cysteine protease blockers are available, including Epoxomicin, lactacystin, MG132, WEHI-842, WEHI-916, and chymostatin.
Phosphoinositide lipid kinases (PIKs) are ubiquitous enzymes that phosphorylate lipids to regulate proliferation, survival, trafficking, and intracellular signaling.The most widely studied PIK classes in 53 parasites are phosphoinositide 3-kinase (PI3K) and phosphatidylinositol 4-kinase (PI4K).Inhibition of these enzymes has been identified as a potential target for the development of antimalarial drugs with desirable activity profiles for the prevention, treatment and elimination of malaria.54 UCT943, imidazopyrazine (KAF156) and aminopyridines are a new class of antimalarial compounds that target PI(4)K and inhibit the intracellular development of multiple Plasmodium species at every stage of host infection.Therefore, targeting (PI3K) and PI(4)K may open new avenues based on targeted drug discovery to identify novel antimalarial drugs.KAF156 is currently in Phase II clinical trials.55,56 MMV048 is a compound with good in vivo prophylactic activity against P. cynomolgi and potential as a transmission blocking drug.MMV048 is currently undergoing Phase IIa clinical trials in Ethiopia.11
For rapid growth in infected red blood cells, Plasmodium species require sufficient amounts of substrates to facilitate their vigorous metabolism.Thus, parasites prepare host erythrocytes by inducing specialized transporters that differ significantly from host cell transporters in uptake and removal of metabolites.Therefore, transporters like carrier proteins and channels are potential targets because of their important roles in the transport of metabolites, electrolytes and nutrients.57 These are the Plasmodium surface anion channel (PSAC) and the parasitic vacuolar membrane (PVM), which provide a continuous diffusion pathway for nutrients into the intracellular parasite.58
PSAC is the most promising target because it is found in different types of nutrients (hypoxanthine, cysteine, glutamine, glutamate, isoleucine, methionine, proline, tyrosine, pantothenic acid and choline) to acquire key roles in intracellular parasites.PSACs have no clear homology to known host channel genes.58,59 Phloridizin, dantrolene, furosemide, and niflunomide are potent anion transporter blockers.Drugs such as glyburide, meglitinide, and tolbutamide inhibit the influx of choline into parasitic-infected red blood cells.60,61
The blood form of Plasmodium falciparum relies almost entirely on glycolysis for energy production, with no energy storage; it relies on the constant uptake of glucose.The parasite converts pyruvate to lactate to produce ATP, which is required for replication inside red blood cells.62 Glucose is first transported into parasitized erythrocytes by a combination of the host cell’s glucose transporter, GLUT1, in the erythrocyte membrane and a parasite-induced ‘new permeation pathway’.63 Glucose is transported into parasites by the Plasmodium falciparum hexose transporter (PFHT).PFHT has some typical sugar transporter characteristics.GLUT1 is selective for D-glucose, while PFHT can transport D-glucose and D-fructose.Thus, differences in GLUT1 and PFHT interactions with substrates suggest that selective inhibition of PFHT is a promising new target for the development of novel antimalarial drugs.64 A long-chain O-3-hexose derivative (compound 3361) inhibits glucose and fructose uptake by PFHT, but it does not inhibit hexose transport by the major mammalian glucose and fructose transporters (GLUT1 and 5).Compound 3361 also inhibited glucose uptake by P. vivax of PFHT.In previous studies, compound 3361 killed P. falciparum in culture and reduced P. berghei reproduction in mouse models.65
Plasmodium blood grouping is largely dependent on anaerobic glycolysis for growth and development.60 Parasite-infected red blood cells absorb glucose 100 times faster than uninfected red blood cells.The parasite metabolizes glucose through glycolysis to lactate, which is exported from the parasite via lactate: an H+ symporter mechanism into the external environment.66 Lactate export and glucose uptake are critical for maintaining energy requirements, intracellular pH, and parasite osmotic stability. Lactate:H+ symporter system inhibition is a promising new target for the development of new drugs.Several compounds, such as MMV007839 and MMV000972, kill asexual blood-stage P. falciparum parasites by inhibiting the lactate:H+ transporter.67
Like other cell types, red blood cells maintain low internal Na+ levels.However, parasites increase the permeability of the erythrocyte membrane and facilitate Na+ entry, leading to an increase in the erythrocyte cytoplasmic Na+ concentration to the level of the extracellular medium.Thus, parasites find themselves in high Na+ media and must expel Na+ ions from their plasma membrane to maintain low cytoplasmic Na+ levels in order to survive despite their presence in intracellular sites.In this case, Na+ influx to the parasite is regulated by using the P-type ATPase transporter (PfATP4), which acts as the parasite’s primary Na+-efflux pump mechanism, as shown in Figure 3.68, inhibiting this transporter It will lead to an increase in the amount of Na+ inside the parasite, which will eventually lead to the death of the malaria parasite.Several compounds, including sipagamin in phase 2, (+)-SJ733 in phase 1, and KAE609 in phase 2, have a mechanism of action that targets PfATP4.67,69
Figure 3. Proposed mechanism of parasite-induced PfATP4 and V-type H+-ATPase in infected erythrocyte death following cipargamin inhibition.
Plasmodium species control their Na+ levels by using the P-type ATPase transporter.It also imports H+ through a similar pathway.To regulate the increasing H+ concentration and maintain an intracellular pH of 7.3, the malaria parasite uses a complementary V-type ATPase transporter to expel H+.Developing a new drug is a promising goal.MMV253 inhibits V-type H+ ATPase as its mechanism of action by mutation selection and whole-genome sequencing.70,71
Aquaporin-3 (AQP3) is an aquaglycerol channel protein that facilitates the movement of water and glycerol in mammalian cells.AQP3 is induced in human hepatocytes in response to parasite infection and has an important role in parasite replication.AQP3 provides access to glycerol into P. berghei and facilitates the parasite’s replication in the asexual erythrocyte stage.72 Genetic depletion of AQP3 significantly suppressed parasite burden in the liver stage of P. berghei.Furthermore, treatment with the AQP3 inhibitor auphen reduced P. berghei parasitemia burden in hepatocytes and P. falciparum parasitemia in erythrocytes, suggesting that host proteins play critical roles in different life stages of the parasite .73 Most intriguingly, disruption of AQP3 in genetic mice is not lethal, suggesting that the host protein has a potential new therapeutic target.This work increases our understanding of host liver processes affected by Plasmodium infection and highlights the potential of these processes as future antimalarial drugs.71,72
Phospholipids play a key role in the intra-erythrocyte life cycle of Plasmodium falciparum, both as structural components of membranes and as regulatory molecules that regulate the activities of various enzymes.These molecules are essential for parasite reproduction inside red blood cells.After erythrocyte invasion, phospholipid levels increase, of which phosphatidylcholine is the major lipid in their cell membrane components.Parasites synthesize phosphatidylcholine de novo using choline as a precursor.This de novo pathway is critical for parasite growth and survival.Inhibits choline transport into parasites and inhibits phosphatidylcholine biosynthesis, resulting in parasite death.74 Albitiazolium, a drug that has entered Phase II trials, works primarily by inhibiting the transport of choline into the parasite.Albitiazolium accumulates up to 1000-fold in Plasmodium and inhibits parasite growth without relapse.It is effective in harsh conditions.Notably, a single injection cured high parasitemia levels.75,76
Phosphocholine cytidyltransferase is the rate-limiting step in the de novo biosynthesis of phosphatidylcholine.77 The diquaternary ammonium compound G25 and the dicationic compound T3 inhibit phosphatidylcholine synthesis in parasites.G25 is 1000-fold less toxic to mammalian cell lines.These drugs are key lead compounds in antimalarial drug discovery and development.78,79
A key step in the spread of Plasmodium species in human hosts is the extensive and rapid division of parasite DNA, which depends on the availability of essential metabolites such as pyrimidines.In Plasmodium, pyrimidine nucleotides play critical roles in the synthesis of DNA, phospholipids and glycoproteins.Nucleotide synthesis follows two main pathways: the salvage pathway and the de novo pathway.Dihydroorotate dehydrogenase (DHODH) is an important enzyme that catalyzes the oxidation of dihydroorotate to orotate, the rate-limiting step in de novo pyrimidine synthesis.Therefore, DHODH represents a potentially promising target for antimalarial drug development.80 Human cells acquire pyrimidines by rescuing already formed pyrimidines or by de novo synthesis.If the de novo biosynthetic pathway is inhibited, the cell will rely on the salvage pathway and the cell will not die.However, inhibition of de novo pyrimidine biosynthesis in parasites results in the death of these cells because the malaria parasite lacks a pyrimidine salvage pathway, which makes the parasite vulnerable to inhibition by DHODH.81 DSM190 and DSM265 are selective inhibitors of the parasite DHODH enzyme, which is currently in Phase 2 clinical trials.P218 is a DHODH inhibitor effective against all pyrimethamine-resistant strains currently in Phase 1.KAF156 (Ganaplacide) is currently in a Phase 2b clinical trial with phenylfluorenol.82
Isoprenoids are required for post-translational lipid modification of proteins and asexual replication of Plasmodium falciparum.Isoprenoids are synthesized from the five-carbon precursor isopentyl diphosphate (IPP) or its isomer, dimethylallyl diphosphate (DMAPP), by one of two independent pathways.Mevalonate pathway and 2C-methyl-D-erythritol 4-phosphate (MEP) pathway.In most microorganisms, these two pathways are mutually exclusive.Bacteria and Plasmodium falciparum are completely dependent on the MEP pathway, whereas humans are not.Therefore, enzymes in the MEP pathway are explored as potential new therapeutic targets.Plasmodium falciparum 1-deoxy-xylulose-5-phosphate reductoisomerase (pfDxr) catalyzes the rate-limiting step in the MEP pathway, making this parasite enzyme a promising target for the development of novel antimalarial drugs.83,84 PfDXR inhibitors inhibit Plasmodium falciparum.Plasmodium falciparum grows and is nontoxic to human cells.PfDXR is a potential new target in antimalarial drug development.83 Fosmidomycin, MMV019313 and MMV008138 inhibit DOXP reductoisomerase, a key enzyme of the DOXP pathway that is absent in humans.Because inhibition of protein prenylation in Plasmodium disrupts the growth of asexual parasites, this is a potential antimalarial target.85
Prenylated proteins play crucial roles in a variety of cellular processes including vesicle trafficking, signal transduction, regulation of DNA replication, and cell division.This post-translational modification facilitates the binding of intracellular proteins to membranes and facilitates protein-protein interactions.Farnesyltransferase catalyzes the transfer of the farnesyl group, a 15-carbon isoprenoid lipid unit, from farnesyl pyrophosphate to the C-terminus of proteins containing the CaaX motif.Farnesyltransferase is a promising new target for the development of antimalarial drugs because its inhibition kills the parasite.86
Previously, the evolution of resistance to parasites by the farnesyltransferase inhibitor BMS-388,891 tetrahydroquinoline showed mutations in the protein of the peptide substrate-binding domain.In the selection of another tetrahydroquinoline with BMS-339,941, a mutation was found in the farnesyl pyrophosphate binding pocket.In another study, mutations were found in the farnesyltransferase beta subunit of a MMV019066-resistant strain of P. falciparum.Modeling studies have shown that the mutation distorts the key interaction site of the small molecule with the farnesylation active site, resulting in drug resistance.87
One of the promising goals for developing new drugs is to block the P. falciparum ribosome, as well as other parts of the translation machinery responsible for protein synthesis.Plasmodium species have three genomes: nucleus, mitochondria, and acroplasts (from residual chloroplasts).All genomes require translation machinery to function.Protein synthesis inhibitors have significant clinical success as effective antibiotics.Doxycycline, clindamycin, and azithromycin have antimalarial therapeutic utility because they inhibit the ribosomes in the parasite mitochondria and aplastoplasts, rendering these organelles inoperative.88 Interestingly, the P. falciparum ribosome occupies an evolutionary middle ground between prokaryotes and eukaryotes, distinguishing it markedly from the human ribosome and thus providing an important promising new target.Plasmodium falciparum elongation factor 2 (pfEF2) is a component of the ribosome that catalyzes GTP-dependent translocation of ribosomes along messenger RNA and is essential for protein synthesis in eukaryotes.PfEF2 was isolated as a new target for antimalarial drug development.87,89
Inhibition of protein synthesis Take the discovery of sordarin, a natural product that selectively blocks fungal protein synthesis by inhibiting yeast eukaryotic elongation factor 2.Similarly, M5717 (formerly DDD107498), a selective inhibitor of the 80S ribosome-interacting PfEF2, is currently in phase 1 studies, validating the potential of PfEF2 as an effective target for antimalarial drugs.88,90
The main features of severe malaria are the sequestration of parasite-infected erythrocytes, inflammation, and blockage of microvasculature.Plasmodium falciparum uses heparan sulfate as it attaches to the endothelium and other blood cells, causing obstruction of blood flow.Inhibiting these abnormal cells and pathogen-drug interactions restores blocked blood flow and affects parasite growth.91
Several studies have shown that sevuparin, an anti-adhesion polysaccharide made from heparin, has antithrombin-eliminating effects.Sevuparin inhibits merozoite invasion into erythrocytes, binding of infected erythrocytes to uninfected and infected erythrocytes, and binding to vascular endothelial cells.Furthermore, sevuparin binds to the N-terminal extracellular heparan sulfate-binding structure of Plasmodium falciparum erythrocyte membrane protein 1, Duffy-binding-like domain 1α (DBL1α), and is thought to be an important factor in sequestering infected erythrocytes.92,93 Some Table 2 summarizes clinical trials at various stages.
Post time: Mar-24-2022