Plasmodium falciparum: Effects of Proteinase Inhibitors on Globin Hydrolysis by Cultured Malaria Parasites

Rosenthal, P

doi:10.1006/expr.1995.1033

Cited by 130 publications

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“…The free parasites were mixed with PBS-Glucose (5.4%), and subjected to three freeze-thaw cycles (2 70 8C / þ 37 8C). The final homogenate was used in the hemoglobin hydrolysis inhibition assay [26].…”

Section: Antimalarial Assaysmentioning

confidence: 99%

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Synthesis and antimalarial activity of novel chiral and achiral benzenesulfonamides bearing 1, 3, 4-oxadiazole moieties

Zareef

Iqbal

Domínguez

et al. 2007

Journal of Enzyme Inhibition and Medicinal Chemistry

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Section: Antimalarial Assaysmentioning

confidence: 99%

“…The incubations were carried out at 37 8C for 18 h and the reactions were stopped by addition of reduced sample buffer. The degree of digestion was evaluated electrophoretically by SDS-PAGE [26] and the intact globin bands were analysed by densitometry. A DMSO control was electrophoresced at the same time.…”

Section: Antimalarial Assaysmentioning

confidence: 99%

Synthesis and antimalarial activity of novel chiral and achiral benzenesulfonamides bearing 1, 3, 4-oxadiazole moieties

Zareef

Iqbal

Domínguez

et al. 2007

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…Of those four, P. falciparum accounts for over 95% of all malaria cases, mainly in Africa, and children under 5 years of age are among the most vulnerable to malaria infection [1]. It has been shown that hemoglobin catabolism, which takes place in an acidic food vacuole, is essential for parasite survival, both in culture and in animal models [2][3][4]. Besides asparticproteases, three cysteine proteases (falcipain-1, -2, and -3) and one metalloprotease (falcilysin) have also been identified to digest hemoglobin in the food vacuole [5][6][7][8].…”

Section: Introductionmentioning

confidence: 99%

In Silico Screening of Antimalarial From Indonesian Medicinal Plants Database to Plasmepsin Target

Rifai

Hayun

Yanuar

2017

Asian J Pharm Clin Res

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Objective: Malaria is a disease that impacts millions of people annually. Among the enzymes, plasmepsin is the main enzyme in the plasmodium life cycle that degrades hemoglobin during the erythrocytic phase in the food vacuole. Recently, pharmaceutical industries have been trying to develop therapeutic agents that can cure malaria through the discovery of new plasmepsin inhibitor compounds. One of the developing approaches is the in silico method. Methods:The chosen in silico screening method in this experiment is a structure-based screening using GOLD software and the Indonesian medicinal plants database.Results: From ten in silico screening runs, three of the compounds always ranked in the top ten. These three compounds are trimyristin, cyanidin 3,5-di-(6-malonylglucoside), and isoscutellarein 4'-methyl ether 8-(6"-n-butylglucuronide). Another compound that emerged with high frequency is cyanidin 3,5-di-(6-malonylglucoside). Conclusions:Based on the results obtained from this screening, 11 inhibitor candidates are expected to be developed as antimalarial. These compounds are trimyristin; cyanidin 3,5-di-(6-malonylglucoside); isoscutellarein 4'-methyl ether 8-(6"-n-butylglucuronide); cyanidin 3-(6"-malonylglucoside)-5-glucoside; multifloroside; delphinidin 3-(2-rhamnosyl-6-malonylglucoside); delphinidin 3-(6-malonylglucoside)-3',5'-di-(6-p-coumaroylglucoside); cyanidin 3-[6-(6-sinapylglucosyl)-2-xylosylgalactoside; kaempferol 3-glucosyl-(1-3)-rhamnosyl-(1-6)-galactoside; sanggenofuran A; and lycopene with a GOLD score range from 78.4647 to 98.2836. Two of them, Asp34 and Asp214, bind with all residues in the catalytic site of plasmepsin.

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“…The four plasmepsins found in the food vacuole of P. falciparum are PfPM1, PfPM2, PfPM4, and the histoaspartic protease (HAP) (3,4). It is now believed that the enzymes from P. vivax (PvPM4), P. ovale (PoPM4), and P. malariae (PmPM4) are orthologs of PfPM4 (5 (3,(6)(7)(8)(9). Therefore, the PfPM4 orthologs would be excellent targets for a single drug therapy directed at all four plasmodium species (4).…”

Section: Introductionmentioning

confidence: 99%

“…been shown to impede growth of the parasite in culture (3,(6)(7)(8)(9). Therefore, the PfPM4 orthologs would be excellent targets for a single drug therapy directed at all four plasmodium species (4).…”

mentioning

confidence: 99%

Analysis of Binding Interactions of Pepsin Inhibitor-3 To Mammalian and Malarial Aspartic Proteases

et al. 2007

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The nematode Ascaris suum primarily infects pigs, but also causes disease in humans. As part of its survival mechanism in the intestinal tract of the host, the worm produces a number of protease inhibitors, including pepsin inhibitor-3 (PI3), a 17 kDa protein. Recombinant PI3 expressed in E. coli has previously been shown to be a competitive inhibitor of a sub-group of aspartic proteinases: pepsin, gastricsin and cathepsin E. The previously determined crystal structure of the complex of PI3 with porcine pepsin (p. pepsin) showed that there are two regions of contact between PI3 and the enzyme. The first three N-terminal residues (QFL) bind into the prime side of the active site cleft and a polyproline helix (139)(140) in the C-terminal domain of PI3 packs against residues 289-295 that form a loop in p. pepsin. Mutational analysis of both inhibitor regions was conducted to assess their contributions to the binding affinity for p. pepsin, human pepsin (h. pepsin) and several malarial aspartic proteases, the plasmepsins. Overall, the polyproline mutations have a limited influence on the K i values for all the enzymes tested, with the values for p. pepsin remaining in the low nanomolar range. The largest effect was seen with a Q1L mutant, with a 200-fold decrease in K i for plasmepsin 2 from Plasmodium falciparum (PfPM2). Thermodynamic measurements of the binding of PI3 to p. pepsin and PfPM2 showed that inhibition of the enzymes is an entropy-driven reaction. Further analysis of the Q1L mutant showed that the increase in binding affinity to PfPM2 was due to improvements in both entropy and enthalpy.There are over 300 million cases of malaria every year, resulting in at least one million deaths annually (World Health Organization, 2006). Malaria is found in tropical and sub-tropical regions of the world and is caused by one of four species of the plasmodium parasite: P. falciparum, P. vivax, P. ovale, and P. malariae. P. falciparum is the deadliest of the four species and P. vivax is the most common, responsible for 40% to 50% of cases in Latin America and Asia.During the intraerythrocytic stage of the plasmodium parasite's lifecycle in the human host, up to 75% of host cell hemoglobin is degraded (1). In P. falciparum several proteases have been identified in the food vacuole that are involved in hemoglobin degradation, including a family of aspartic proteases known as the plasmepsins (2,3). The four plasmepsins found in the food vacuole of P. falciparum are PfPM1, PfPM2, PfPM4, and the histoaspartic protease (HAP) (3,4). It is now believed that the enzymes from P. vivax (PvPM4), P. ovale (PoPM4), and P. malariae (PmPM4) are orthologs of PfPM4 (5 (3,(6)(7)(8)(9). Therefore, the PfPM4 orthologs would be excellent targets for a single drug therapy directed at all four plasmodium species (4).Most large, proteinaceous inhibitors of aspartic proteases have been isolated from plants (10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20). For this study, we have analyzed the inhibition of aspartic proteases by a 17 kD inhi...

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Plasmodium falciparum: Effects of Proteinase Inhibitors on Globin Hydrolysis by Cultured Malaria Parasites

Cited by 130 publications

References 0 publications

Synthesis and antimalarial activity of novel chiral and achiral benzenesulfonamides bearing 1, 3, 4-oxadiazole moieties

Synthesis and antimalarial activity of novel chiral and achiral benzenesulfonamides bearing 1, 3, 4-oxadiazole moieties

In Silico Screening of Antimalarial From Indonesian Medicinal Plants Database to Plasmepsin Target

Analysis of Binding Interactions of Pepsin Inhibitor-3 To Mammalian and Malarial Aspartic Proteases

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