Plasmepsins as potential targets for new antimalarial therapy
Identifieur interne : 004209 ( Main/Exploration ); précédent : 004208; suivant : 004210Plasmepsins as potential targets for new antimalarial therapy
Auteurs : Karolina Ersmark [Suède] ; Bertil Samuelsson [Suède] ; Anders Hallberg [Suède]Source :
- Medicinal Research Reviews [ 0198-6325 ] ; 2006-09.
English descriptors
- Teeft :
- 1sme, Acidic, Acta, Active site, Adaptive inhibitor, Amide, Amino, Amino acids, Analog, Anopheles, Antimalarial, Antimalarial agents, Antimalarial drugs, Antimalarial therapy, Antimicrob agents chemother, Aspartic, Aspartic protease, Aspartic protease inhibitors, Aspartic proteases, Aspartic proteinase, Aspartic proteinases, Aspartyl, Assay, Basic hydroxyethylamine inhibitors, Benzyl, Binding cavity, Binding cleft, Binding mode, Biochem, Biochem parasitol, Biol, Biol chem, Bioorg, Catalytic, Catalytic aspartic acids, Catalytic water molecule, Cathepsin, Cell culture, Cell permeability, Central scaffold, Chem, Chem lett, Chloroquine, Comb chem, Combinatorial, Combinatorial libraries, Crystal structure, Crystal structures, Cysteine, Degradation, Different plasmepsins, Docking, Drug design, Drug discovery, Drug intervention, Drug targets, Erickson, Ersmark, Erythrocyte, Erythrocytic, Erythrocytic stage, Exibility, Falciparum, Febs lett, Food vacuole, Food vacuole plasmepsins, Genome, Gluzman, Hallberg, Hallberg figure, Hallberg table, Hamelink, Heme, Hemoglobin, Hemoglobin catabolism, Hemoglobin degradation, Hemoglobin metabolism, High potency, Higher potency, Homology, Human aspartic proteases, Human malaria parasite plasmodium falciparum, Human plasmodium species, Hydrogen bond, Hydrogen bonds, Hydroxyethylamine, Hydroxyl, Hydroxyl group, Inhibitor, Inhibitory potency, Isostere, Kiso, Lett, Life cycle, Malaria, Malaria parasite plasmodium falciparum, Malaria parasites, Malarial, Malarial aspartic protease plasmepsin, Medicinal, Medicinal chemistry, Moiety, Mosquito, Natural products, Nezami, Nonpeptide, Nonpeptide inhibitors, Nonpeptide plasmepsin inhibitors, Parasite, Parasite growth, Parasite life cycle, Parasite resistance, Parasitol, Pathway, Pepstatin, Peptidomimetic, Peptidomimetic inhibitors, Peptidomimetic plasmepsin inhibitors, Permeability, Plasmepsin, Plasmepsin inhibitors, Plasmepsin selectivity, Plasmepsins, Plasmodium, Plasmodium falciparum, Plasmodium falciparum plasmepsin, Plasmodium species, Potency, Potent, Potent inhibitor, Potent inhibitors, Prime side, Proc natl acad, Protease, Protease inhibitors, Proteinase, Rational design, Renin, Ridley, Ring nitrogen, Rosenthal, Samuelsson, Selectivity, Sequence identity, Side chain, Side chains, Silva, Statine, Statines, Subsite, Subsites, Substituent, Substituents, Substrate preferences, Trends parasitol, Trophozoite, Uncomplexed, Unsymmetrical, Uppsala, Uppsala university, Vacuole, Vivax, Vrang, Water molecule, World health organization, Yowell.
Abstract
Malaria is one of the major diseases in the world. Due to the rapid spread of parasite resistance to available antimalarial drugs there is an urgent need for new antimalarials with novel mechanisms of action. Several promising targets for drug intervention have been revealed in recent years. This review addresses the parasitic aspartic proteases termed plasmepsins (Plms) that are involved in the hemoglobin catabolism that occurs during the erythrocytic stage of the malarial parasite life cycle. Four Plasmodium species are responsible for human malaria; P. vivax, P. ovale, P. malariae, and P. falciparum. This review focuses on inhibitors of the haemoglobin‐degrading plasmepsins of the most lethal species, P. falciparum; Plm I, Plm II, Plm IV, and histo‐aspartic protease (HAP). Previously, Plm II has attracted the most attention. With the identification and characterization of new plasmepsins and the results from recent plasmepsin knockout studies, it now seems clear that in order to achieve high‐antiparasitic activities in P. falciparum‐infected erythrocytes it is necessary to inhibit several of the haemoglobin‐degrading plasmepsins. Herein we summarize the structure–activity relationships of the Plm I, II, IV, and HAP inhibitors. These inhibitors represent all classes which, to the best of our knowledge, have been disclosed in journal articles to date. The 3D structures of inhibitor/plasmepsin II complexes available in the protein data bank are briefly discussed and compared. © 2006 Wiley Periodicals, Inc. Med Res Rev, 26, No. 5, 626–666, 2006
Url:
DOI: 10.1002/med.20082
Affiliations:
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table</term><term>Hamelink</term><term>Heme</term><term>Hemoglobin</term><term>Hemoglobin catabolism</term><term>Hemoglobin degradation</term><term>Hemoglobin metabolism</term><term>High potency</term><term>Higher potency</term><term>Homology</term><term>Human aspartic proteases</term><term>Human malaria parasite plasmodium falciparum</term><term>Human plasmodium species</term><term>Hydrogen bond</term><term>Hydrogen bonds</term><term>Hydroxyethylamine</term><term>Hydroxyl</term><term>Hydroxyl group</term><term>Inhibitor</term><term>Inhibitory potency</term><term>Isostere</term><term>Kiso</term><term>Lett</term><term>Life cycle</term><term>Malaria</term><term>Malaria parasite plasmodium falciparum</term><term>Malaria parasites</term><term>Malarial</term><term>Malarial aspartic protease plasmepsin</term><term>Medicinal</term><term>Medicinal chemistry</term><term>Moiety</term><term>Mosquito</term><term>Natural products</term><term>Nezami</term><term>Nonpeptide</term><term>Nonpeptide 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nitrogen</term><term>Rosenthal</term><term>Samuelsson</term><term>Selectivity</term><term>Sequence identity</term><term>Side chain</term><term>Side chains</term><term>Silva</term><term>Statine</term><term>Statines</term><term>Subsite</term><term>Subsites</term><term>Substituent</term><term>Substituents</term><term>Substrate preferences</term><term>Trends parasitol</term><term>Trophozoite</term><term>Uncomplexed</term><term>Unsymmetrical</term><term>Uppsala</term><term>Uppsala university</term><term>Vacuole</term><term>Vivax</term><term>Vrang</term><term>Water molecule</term><term>World health organization</term><term>Yowell</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Malaria is one of the major diseases in the world. Due to the rapid spread of parasite resistance to available antimalarial drugs there is an urgent need for new antimalarials with novel mechanisms of action. Several promising targets for drug intervention have been revealed in recent years. This review addresses the parasitic aspartic proteases termed plasmepsins (Plms) that are involved in the hemoglobin catabolism that occurs during the erythrocytic stage of the malarial parasite life cycle. Four Plasmodium species are responsible for human malaria; P. vivax, P. ovale, P. malariae, and P. falciparum. This review focuses on inhibitors of the haemoglobin‐degrading plasmepsins of the most lethal species, P. falciparum; Plm I, Plm II, Plm IV, and histo‐aspartic protease (HAP). Previously, Plm II has attracted the most attention. With the identification and characterization of new plasmepsins and the results from recent plasmepsin knockout studies, it now seems clear that in order to achieve high‐antiparasitic activities in P. falciparum‐infected erythrocytes it is necessary to inhibit several of the haemoglobin‐degrading plasmepsins. Herein we summarize the structure–activity relationships of the Plm I, II, IV, and HAP inhibitors. These inhibitors represent all classes which, to the best of our knowledge, have been disclosed in journal articles to date. The 3D structures of inhibitor/plasmepsin II complexes available in the protein data bank are briefly discussed and compared. © 2006 Wiley Periodicals, Inc. Med Res Rev, 26, No. 5, 626–666, 2006</div></front></TEI><affiliations><list><country><li>Suède</li></country><region><li>East Middle Sweden</li><li>Svealand</li></region><settlement><li>Uppsala</li></settlement><orgName><li>Université d'Uppsala</li></orgName></list><tree><country name="Suède"><region name="Svealand"><name sortKey="Ersmark, Karolina" sort="Ersmark, Karolina" uniqKey="Ersmark K" first="Karolina" last="Ersmark">Karolina Ersmark</name></region><name sortKey="Hallberg, Anders" sort="Hallberg, Anders" uniqKey="Hallberg A" first="Anders" last="Hallberg">Anders Hallberg</name><name sortKey="Hallberg, Anders" sort="Hallberg, Anders" uniqKey="Hallberg A" first="Anders" last="Hallberg">Anders Hallberg</name><name sortKey="Hallberg, Anders" sort="Hallberg, Anders" uniqKey="Hallberg A" first="Anders" last="Hallberg">Anders Hallberg</name><name sortKey="Samuelsson, Bertil" sort="Samuelsson, Bertil" uniqKey="Samuelsson B" first="Bertil" last="Samuelsson">Bertil Samuelsson</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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