Compounds Targeting Entamoeba histolytica and Its Biological Membrane

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Compounds Targeting Entamoeba histolytica and Its Biological Membrane

This entry is adapted from the peer-reviewed paper 10.3390/membranes12040396

Entamoeba histolytica membrane cytosolic proteins compounds

1. Introduction

Amoebiasis is the third most common parasitic cause of morbidity and mortality, particularly in countries with poor hygienic settings in central and south America, Africa, and India ^[1]^[2]. This disease is caused by Entamoeba histolytica, a protozoan parasite that infects approximately 50 million people worldwide, resulting in an estimated 70,000 deaths every year ^[3]. This parasite has two major life cycle stages: the trophozoite and the cyst. The most common infection route is ingesting contaminated food and water, where the infection is concentrated in the intestine and organs such as the liver, lungs, and brain. While 90% of infected individuals are asymptomatic, the infection may also lead to severe complications, such as colitis with bloody diarrhea, liver abscesses, and colonic perforation ^[4].

Metronidazole is the most often prescribed and successful drug to treat E. histolytica. The modes of action involve four steps: passive diffusion into the cell membrane, reduction of nitro groups to nitro radicals by ferredoxin or flavodoxin (intracellular transport protein), generation of toxic metabolites, and finally the reaction of the metabolites with DNA and formation of adducts with guanosine ^[5]^[6]. This mode of action of metronidazole results in the E. histolytica death. However, there are drawbacks to metronidazole therapy such as its adverse side effects, qualities of being carcinogenic and mutagenic, alcohol intolerance, and problems when used during pregnancy and lactation ^[7]^[8]. Furthermore, the increasing concern of parasites developing resistance is also one of the drawbacks of this drug ^[7].

Biological membranes are a successful evolutionary result of a long-term natural selection process and one of the most complex structures that allow life to exist ^[9]^[10]. Biological membranes have various functions but the main function is to act as a key platform for the entire network of cellular processes, such as for cell proliferation, adhesion, migration, and intracellular trafficking, thus being appealing targets for drug treatment ^[11]. Apart from that, the phospholipids that are part of biological membranes are the necessary components for fusing vesicles and fundamental for the phagocytosis of E. histolytica.

2. Biological Membranes’ Protein

2.1. Thioredoxin Reductase

Thioredoxin reductase (TrxR) is one of the enzymes found in the surface proteome of E. histolytica. It is considered a membrane enzyme containing selenocysteine, a rare amino acid ^[12]. The presence of this amino acid makes it a selenoprotein. The observation was confirmed using western blotting and immunofluorescence microscopy ^[13]. The function of the TrxR is to catalyze the reversible transfer of reducing equivalents between reduced nicotinamide adenine dinucleotide phosphate (NADPH) and thioredoxin, a small protein that performs critical metabolic processes in maintaining the intracellular redox balance ^[14]. TrxR is often paired with thioredoxin, forming a thioredoxin system, a ubiquitous oxidoreductase system with antioxidant and redox regulatory roles ^[15].

The systems take part in several activities such as the regulation of enzymatic activities; repairing of oxidized proteins; affording of reducing equivalents for DNA synthesis; and cellular transcription, growth, and apoptosis ^[14]^[16]^[17]. This enzyme is a potential drug target because it exhibits pharmacokinetics, an availability of a three-dimensional structure, favorable physiochemical properties, participation in significant pathways, rich interactions, and broad-spectrum conservation ^[18].

2.2. Cysteine Protease

The following enzyme found on the membrane of E. histolytica is a cysteine protease, which is critically implicated in the pathogenesis of protozoic infections ^[19]. It contains the Cys–His–Asn triad at the active site. According to Tusar et al. (2021) ^[20] this enzyme uses the reactive site cysteine as a catalytic nucleophile and histidine to hydrolyze the peptide bond. These parasite-derived cysteine proteases also play critical roles in hemoglobin hydrolysis; the breakdown of RBC proteins; immunoevasion; enzyme activation; virulence; tissue and cellular invasion; and excystment, hatching, and moulting ^[21]^[22]. These functional diversities are being contributed to by their unique nucleophilicity, adaptability to different substrates, stability in different biological environments, and regulation ^[23]. Due to their critical functions in many parasites’ life cycles and pathogenicity, these cysteine proteases are found suitable to be the target molecules to combat E. histolytica growth by blocking interactions that cause these proteases’ inactivity.

2.3. Protein Phosphatases

Protein phosphatase plays a vital role in regulating any organism, including this parasite; thus, it is considered a potential therapeutic target. In E. histolytica, this peripheral membrane protein can also be found in several places such as the cytoplasm, plasma membrane, chloroplast, nuclear, and cytoplasmic ^[24]. A dedicated database and web server, namely ‘EhPPTome’, was developed by Anwar and Gourinath (2017) ^[24] which incorporates information about 250 protein phosphatases in E. histolytica that helps to improve the understanding of the background protein phosphatases. The EhPPTome includes the classification of phosphatases into the superfamily and families, their localization, their biological function, and their KEGG pathway. This understanding makes phosphatases a potential target for E. histolytica.

2.4. Triosephosphate Isomerase

Triosephosphate isomerase (TIM) is one of the proteins indirectly associated with the plasma membrane of E. histolytica ^[13].This protein is involved in the first step of the subpathway that synthesizes D-glyceraldehyde 3-phosphate from the glycerone phosphate of glucogenesis.

2.5. Alcohol Dehydrogenase

Alcohol dehydrogenase (ADH) is a type of enzyme found in two places in E. histolytica, which are in the cytoplasm and at the peripheral surface of the amoeba’s trophozoites ^[13]. This enzyme is crucial in the amoebic fermentation pathway as it helps to metabolize the ethanol to produce energy, notably in the E. histolytica, as it lacks energy-producing mitochondria ^[25]^[26].

2.6. GTPases

GTPases are molecular switches that regulate cellular processes such as cell polarity, gene transcription, microtubule dynamics, the cell cycle, cell migration, and vesicle trafficking ^[9]^[27].

2.7. KERP1

The KERP1 protein, which is rich in lysine and glutamic acid, is a virulence factor expressed on the cell surface in the human pathogen E. histolytica ^[28]. Microscopic data showed that KERP1 accumulated in vesicles of different morphologies that appeared to move randomly. They depended on the actin-rich cytoskeleton but were independent of the antegrade transport. The protein has been associated with endomembrane transport components such as multivesicular endosomes/bodies (MVB) and specific phosphatidylinositols (PtdIns). The subcellular localization of KERP1 compared to known markers for vesicle transport showed the intracellular transit of KERP1 as a cargo molecule and during interaction with host pathogens from the parasite to the external environment.

2.8. Protein Kinase

These protein kinases are known to regulate multiple cellular processes such as metabolism, motility, and endocytosis through the phosphorylation of specific target proteins that form a communication system that sends extracellular signals for an adaptive response to the intracellular environment. Furthermore, the kinome of the parasite is composed of several conserved kinases with an unusual domain architecture. About one-third of kinome codes for transmembrane kinases (TMK) is proposed to help the parasite sense and adapt to the gut environment, which is constantly changing.

The abundant number of kinases that E. histolytica possesses allows scholars to assume that the regulation of cellular functions by phosphorylation/dephosphorylation processes is critical. The genome of this parasite codes for 331 putative protein kinases, which account for 3.7% of the proteome ^[29]. Protein kinases are the second most important drug target group after the G protein-coupled receptor due to their function in parasite proliferation and invasive disease formation ^[30].

2.9. Nickman Pick Type (NPC)

Research on lipid synthesis and metabolic pathways may be a promising area for developing effective vaccines and antiparasitic drugs. Of these, cholesterol is a fundamental molecule for the expression of virulence that enhances the trophozoite’s adherence to the host cells and extracellular matrix ^[31]. However, the trophozoites of E. histolytica lack enzymes for cholesterol and fatty acids synthesis, which they need to scavenge from the host or culture medium by specific mechanisms.

2.10. Interferon-Gamma (IFN-γ) Receptor

Martinez-Hernandez et al. (2019) ^[32] identified IFN-γ receptor-like proteins on the surface of E. histolytica trophozoites using anti-IFN-γ receptor 1 (IFN-γR1) antibody through several techniques such as immunofluorescence, western blot, protein sequencing, and in silico analyses. The protein was found to modulate parasite virulence. The surface IFNγ receptor-like protein is functional and may play a role in disease pathogenesis and/or immune evasion ^[33]. The coupling of human IFN-γ to the IFN-γ receptor-like protein on live E. histolytica trophozoites had significantly upregulated the expression of E. histolytica cysteine protease A1 (EhCP-A1), EhCP-A2, EhCP-A4, EhCP-A5, amebapore A (APA), cyclooxygenase 1 (Cox-1), Gal-lectin (Hgl), and peroxiredoxin (Prx) in a time-dependent manner ^[33]. Furthermore, IFNγ signaling through the IFNγ receptor-like protein increased the erythrophagocytosis of human red blood cells of E. histolytica. However, this signaling was abolished by the STAT1 inhibitor fludarabine. In addition, the exogenous IFNγ potentiates E. histolytica chemotaxis, kills colon carcinoma (Caco2) and Hep G2 colonic liver cells, and increases amoebic liver abscess (ALA) formation. Thus, targeting this receptor protein could disrupt the pathway and combat the E. histolytica.

2.11. ERGIC53-like Protein

The ERGIC53-like protein is a type I membrane protein. It belongs to the class of intracellular cargo receptors and is essential for intracellular glycoprotein transport. They are involved in the transport of glycoproteins between the endoplasmic reticulum and the Golgi body. According to Khan and Suguna (2019) ^[34], the structure of the domain bears a resemblance to mammalian and yeast orthologs ERGIC-53 and Emp46, respectively. However, there are significant changes in the carbohydrate-binding site. The difference that the ERGIC53 protein of E. histolytica portrays is that it may probably have potential as a drug target.

3. Potential Compound

3.1. Natural Products

Plants are a popular choice in developing countries as they can be considered safe and available at a low cost. The study conducted by Mehdi et al. (2019) ^[35] had shown experiments using Tamarindus indica. The T. indica extract in ethanolic and aqueous form was used against infected rats with E. histolytica. The T. indica contains many functional compounds such as flavonoids, alkaloids, tannins, phenols, and many more, making it suitable to kill E. histolytica. The alkaloids present in the plant extract had broken down the cell membrane of the E. histolytica, which causes the cell contents, such as the proteins and fat, to excrete. Besides, it also interferes with the DNA of E. histolytica. Both effects of the alkaloids result in the death of the E. histolytica.

Furthermore, tannins, another compound present in T. indica extract, inhibit the transport of proteins and enzymes on the cell membranes. The enzymes’ inhibition mechanisms are through the collaboration of tannins and the phenols, which results in protein precipitation through the formation of hydrogen bonds between hydroxyl phenols, nitrogen compounds, and proteins. The results showed the reduced number of E. histolytica in vivo when the dose of 500 mg/kg of the extract was used during the treatment of the rats. Apart from that, the extract also helps to repair the intestine tissue. This event can be seen from the histopathological section of the colon of the rats, where a moderate increase in the number of goblet cells and thickening of the mucosa of the colon when administered with T. indica extracts occur ^[35]. Increased goblet cells indicated that the immunity increased in the mucosa of the colon as well as the production of anti-microbial antibodies. Both events showed that this extract is a good indicator for curing patients with E. histolytica infection.

Another natural product used against E. histolytica is a Camellia sinensis extract. A study conducted by Shaker et al. (2018) ^[36] showed that C. sinensis extract is suitable for targeting the E. histolytica. It contains many beneficial compounds such as alkaloids, phenols, tannins, flavonoids, glycosides, saponins, and resins that kill E. histolytica. Both natural products are effective against E. histolytica. However, the specific biological membranes involved are not reported, which requires a deeper understanding of the mechanism of action.

3.2. Synthetic Compounds

Synthetic drugs are chemically produced in the laboratory and their chemical structures can be different or identical to naturally occurring drugs ^[37]. Research conducted by Inam et al. (2016) ^[38] had designed and synthesized a series of hydrazone hybrids (H1 Single bond H30) targeting E. histolytica. They found that the synthesized compound N′-(2-chlorobenzylidene)-4-(2-(dimethylamino) ethoxy) benzohydrazide exhibited promising results against E. histolytica. However, a specific mechanism of action was not published in detail. The compilation of the compounds and target proteins can be found in Table 1.

Table 1. The table below summarizes the compilations of the compounds and target protein.

Reference	Protein Target	Compound
^[39]	Thioredoxin reductase	Auranofin
^[18]	Thioredoxin reductase	(1-(carboxymethyl)-4-(4-methylthiazole-5-carboxamido)-3H-pyrazol-1-ium-3-ide)
^[40]	Thioredoxin reductase	Homalomena aromatica Schott 3,7-dimethylocta-1,6-dien-3-yl acetate, α-methyl-α-(4-methyl-3-pentenyl)-oriranemethanol 7-octadiene-2,6-diol-2,6-dimethyl
^[20]	Cysteine protease	Macrocypins, thyropins, and serpins
^[8]	Protein phosphatases2 a	Calyculin, fostriecin, and okadaic acid
^[41]	Recombinant tyrosine phosphatase regenerating liver	P.T.P. inhibitor o-vanadate
^[42]	Low molecular weight tyrosine phosphatases	Orthovanadate
^[43]	Triosephosphate isomerase	5,5′-[(4-nitrophenyl) methylene] bis(6-hydroxy-2-mercapto-3-methyl-4(3H)-pyrimidinone) or D4
^[26]	Alcohol dehydrogenase	Lab-tested pyrazoline derivatives
^[44]	EhCaBP6	-
^[19]	Rho family GTPases	-
^[45]	KERP1	-
^[46]	Kinase	Dasatinib, bosutinib, ibrutinib, ponatinib, neratinib, and olmutinib
^[45]	EhTMKB1-9	-
^[47]	Src kinases	-
^[48]	Adenosine 5′-phosphosulfate kinase (EhAPSK)	2-(3-fluorophenoxy)- N-[4-(2-pyridyl)thiazol-2-yl] -acetamide, 3-phenyl-N-[4-(2-pyridyl)thiazol-2-yl]-imidazole-4-carboxamide
^[48]	Adenosine 5′-phosphosulfate kinase (EhAPSK)	Auranofin
^[49]	Nickman Pick Type 1	-
^[49]	Nickman Pick Type 2	-
^[32]	Interferon-gamma (IFN-γ) receptor	STAT1 inhibitor fludarabine
^[34]	ERGIC53-like protein	-
^[35]	-	Tamarindus indica flavonoids alkaloids tannins phenols
^[36]	-	Camellia sinensis. alkaloids, phenols, tannins, flavonoids, glycosides, saponins, resins
^[38]	-	N′-(2-chlorobenzylidene)-4-(2-(dimethylamino) ethoxy) benzohydrazide

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