Inhibitors of the Plasmodium Falciparum Parasite Aspartic Protease Plasmepsin II As Potential Antimalarial Agents

Boss, Christoph; Richard‐Bildstein, Sylvia; Weller, Thomas; Fischli, Walter; Meyer, Solange; Binkert, Christoph A.

doi:10.2174/0929867033457674

Cited by 99 publications

(119 citation statements)

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“…Rather, our data suggest that pepstatin A is not effective on WT parasites because blockade of plasmepsins is not lethal. Dozens of laboratories have made hundreds of compounds targeted to plasmepsins (25). None is more potent than pepstatin A against isolated enzyme, and all show limited efficacy on cultured parasites.…”

Section: Discussionmentioning

confidence: 99%

Plasmodium falciparum ensures its amino acid supply with multiple acquisition pathways and redundant proteolytic enzyme systems

Istvan

Gluzman

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

328

333

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Degradation of host hemoglobin by the human malaria parasitePlasmodium falciparum is a massive metabolic process. What role this degradation plays and whether it is essential for parasite survival have not been established, nor have the roles of the various degradative enzymes been clearly defined. We report that P. falciparum can grow in medium containing a single amino acid (isoleucine, the only amino acid missing from human hemoglobin). In this medium, growth of hemoglobin-degrading enzyme gene knockout lines (missing falcipain-2 and plasmepsins alone or in combination) is impaired. Blockade of plasmepsins with the potent inhibitor pepstatin A has a minimal effect on WT parasite growth but kills falcipain-2 knockout parasites at low concentrations and is even more potent on falcipain-2, plasmepsin I and IV triple knockout parasites. We conclude that: (i ) hemoglobin degradation is necessary for parasite survival; (ii ) hemoglobin degradation is sufficient to supply most of the parasite's amino acid requirements; (iii ) external amino acid acquisition and hemoglobin digestion are partially redundant nutrient pathways; (iv) hemoglobin degradation uses dual protease families with overlapping function; and (v) hemoglobin-degrading plasmepsins are not promising drug targets.hemoglobin ͉ malaria ͉ protease

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Section: Discussionmentioning

confidence: 99%

Plasmodium falciparum ensures its amino acid supply with multiple acquisition pathways and redundant proteolytic enzyme systems

Istvan

Gluzman

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

328

333

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“…Such efforts discoveries will result in new drugs that are functionally and structurally different from the existing drugs and therefore will overcome existing resistances. Here we have focused on the aspartic protease Plasmepsin II, which is a promising new drug target [4]. Several x-ray structures of PM II have been described previously, but thus far, structure-based drug design has been hampered by the fact that only inhibitors comprising a statine moiety or derivatives thereof have been published.…”

Section: Figurementioning

confidence: 99%

Scaffhold Hopping to Percept the Achiral Compound and Functionalizing on Target Protein Plasmepsin II

Shanmughavel¹

2017

MOJPB

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Malaria is a vector-borne infectious disease caused by protozoan parasites of the genus Plasmodium. Four types of the plasmodium parasite can infect humans; the most serious forms of the diseases are caused by Plasmodium falciparum. Plasmepsin group of enzymes are key enzymes in the life cycle of malarial parasites. Plasmepsin II enzyme is responsible for the formation of the hemozoin through the hemoglobin degradation pathway. Specification of potential drug target by inhibiting Plasmepsin II Enzyme, N-(R-Carboxy-Ethyl)-Alpha-(S)-(2-Phenylethyl) presently used as an inhibitor, to prevent the degradation. Changeover of side chains based on isomeric property of Achiral compounds is aimed to be a new inhibitor for the Plasmepsin II enzyme. Scaffold hopping is an approach used to discover new chemical classes by replacing a portion (the scaffold) of a known compound, while preserving the remaining chemical groups, under the assumption that they are important for biological activity. The main goal of this investigation was to find out the types of combination with the ligand to be the most active in the inhibition of Plasmepsin II enzyme, among the Achiral compounds. Achiral inhibitors revealed exploitation of a new inhibitor observed in Plasmepsin II protein, by Electrostatic potential, binding energy, and bond interactions.

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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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Inhibitors of the Plasmodium Falciparum Parasite Aspartic Protease Plasmepsin II As Potential Antimalarial Agents

Cited by 99 publications

References 0 publications

Plasmodium falciparum ensures its amino acid supply with multiple acquisition pathways and redundant proteolytic enzyme systems

Plasmodium falciparum ensures its amino acid supply with multiple acquisition pathways and redundant proteolytic enzyme systems

Scaffhold Hopping to Percept the Achiral Compound and Functionalizing on Target Protein Plasmepsin II

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

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