Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0024530 (malaria)
 44,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Antimalarial effects might be expected from compounds that modify hemoglobin. Dibromoaspirin and bis(dibromosalicyl) diesters decrease gelation of hemoglobin by specific covalent modification (acetylation and crosslinking) of this protein but do not interfere with oxygen transport. These compounds were toxic to malaria parasites when continuously present in culture, as were drugs with similar pharmacological effects such as indomethacin, ibuprofen, and phenylbutazone. Aspirin and acetaminophen were much less effective. When erythrocytes were pretreated with these compounds prior to parasite exposure, only dibromoaspirin and dibromosalicyl diesters prevented parasite development. The modified hemoglobin was highly resistant to digestion by cathepsin D and parasite proteases, suggesting that covalent modifications of hemoglobin that do not disrupt normal hemoglobin function have antimalarial effects.
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PMID:Inhibition of the growth of Plasmodium falciparum in vitro by covalent modification of hemoglobin. 636 46

The cathepsin D of Plasmodium lophurae was purified using a combination of CM-Sephadex, pepstatin-agarose and Sephadex G-100 chromatography. The plasmodial enzyme was distinct from that of the host red cell and bovine spleen in its low isoelectric point (pI 4.3). The cathepsin D of P. lophurae, as well as plasmodial extracts demonstrating such proteinase activity, were able to digest the membrane proteins of duckling and human red cells at pH 7.4; proteolysis was not inhibited in phosphate-buffered saline by 100 microM pepstatin. Membrane proteins most susceptible to proteolysis were those of the cytoskeleton, notably bands 1 and 2 (spectrin), bands 2.1-2.6 (spectrin-binding proteins) and band 3. Membrane protein degradation by crude plasmodial extracts was partially inhibited by a combination of 10 mM FeCl3, and 10 mM phenylmethylsulfonyl fluoride in phosphate-buffered saline. The changes induced in erythrocyte membrane proteins by exposure to plasmodial cathepsin D parallel the alterations observed in red cell membranes obtained from malaria infected cells. Since the action of the plasmodial protease was confined to the inner surface of the red cell membrane, it is possible that protease-induced modifications in the red cell cytoskeleton could lead to merozoite release.
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PMID:Purification of Plasmodium lophurae cathepsin D and its effects on erythrocyte membrane proteins. 662 18

Intraerythrocytic malaria parasites rapidly degrade virtually all of the host cell hemoglobin. We have cloned the gene for an aspartic hemoglobinase that initiates the hemoglobin degradation pathway in Plasmodium falciparum. It encodes a protein with 35% homology to human renin and cathepsin D, but has an unusually long pro-piece that includes a putative membrane spanning anchor. Immunolocalization studies place the enzyme in the digestive vacuole and throughout the hemoglobin ingestion pathway, suggesting an unusual protein targeting route. A peptidomimetic inhibitor selectively blocks the aspartic hemoglobinase, prevents hemoglobin degradation and kills the organism. We conclude that Plasmodium hemoglobin catabolism is a prime target for antimalarial chemotherapy and have identified a lead compound towards this goal.
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PMID:Molecular characterization and inhibition of a Plasmodium falciparum aspartic hemoglobinase. 831 75

Large numbers of pharmaceutically relevant low-molecular weight compounds can now be synthesized using combinatorial methods. Screening these large libraries of compounds requires high throughput assays. These methods are utilized to search for inhibitors of the aspartyl proteases, plasmepsin II and cathepsin D. Plasmepsin II, a protease found in the malaria parasite, hydrolyzes human hemoglobin, the nutrient source for the parasite and is a new target for anti-malaria therapy. Cathepsin D may be involved in many biological processes and inhibitors would help to clarify the role of cathepsin D in these processes. Plasmepsin II and cathepsin D are approximately 35% identical in amino acid sequence. Therefore, a comparison of the screening results of these two enzymes will be very useful in determining each enzyme's specificity and demonstrating the power of utilizing encoded combinatorial libraries.
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PMID:Screening aspartyl proteases with combinatorial libraries. 956 Dec 44

Blood-feeding parasites, including schistosomes, hookworms, and malaria parasites, employ aspartic proteases to make initial or early cleavages in ingested host hemoglobin. To better understand the substrate affinity of these aspartic proteases, sequences were aligned with and/or three-dimensional, molecular models were constructed of the cathepsin D-like aspartic proteases of schistosomes and hookworms and of plasmepsins of Plasmodium falciparum and Plasmodium vivax, using the structure of human cathepsin D bound to the inhibitor pepstatin as the template. The catalytic subsites S5 through S4' were determined for the modeled parasite proteases. Subsequently, the crystal structure of mouse renin complexed with the nonapeptidyl inhibitor t-butyl-CO-His-Pro-Phe-His-Leu [CHOHCH(2)]Leu-Tyr-Tyr-Ser- NH(2) (CH-66) was used to build homology models of the hemoglobin-degrading peptidases docked with a series of octapeptide substrates. The modeled octapeptides included representative sites in hemoglobin known to be cleaved by both Schistosoma japonicum cathepsin D and human cathepsin D, as well as sites cleaved by one but not the other of these enzymes. The peptidase-octapeptide substrate models revealed that differences in cleavage sites were generally attributable to the influence of a single amino acid change among the P5 to P4' residues that would either enhance or diminish the enzymatic affinity. The difference in cleavage sites appeared to be more profound than might be expected from sequence differences in the enzymes and hemoglobins. The findings support the notion that selective inhibitors of the hemoglobin-degrading peptidases of blood-feeding parasites at large could be developed as novel anti-parasitic agents.
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PMID:Hemoglobin-degrading, aspartic proteases of blood-feeding parasites: substrate specificity revealed by homology models. 1149 96

Plasmodium falciparum is a major causative agent of malaria, a disease of worldwide importance. Inhibition of a hemoglobin degrading P. falciparum aspartic protease Plasmepsin II (Plm II) provides a viable strategy for antimalarial therapy. Linear peptidic inhibitors based on the 4(S)-amino-3(S)-hydroxy-5-phenylpentanoic acid at the P1-P1' positions are known which inhibit Plm II with improved selectivity over cathepsin D. A series of computations were performed in order to gain insight into the interactions of these inhibitors with Plm II. The docking and molecular dynamics simulations were performed on a model ligand/enzyme complex to optimize the variables involved in the generation of ligand/enzyme models. This protocol of docking and molecular dynamics (MD) simulation was then used to derive the ligand-enzyme complexes of the molecules used in the present study. Different modes of binding of pepstatin and the three linear inhibitors were studied. Molecular dynamics simulation was performed at 300K for 100ps with a time step of Ifs. The structural effects of ligand binding were analyzed on the basis of hydrogen bond interactions, interaction energies, hydrophobic contacts and RMS deviations in the resulting energy-minimized structures of the receptor-ligand complexes. The results indicate that hydrophobic and hydrogen bonding interactions are responsible for selective inhibition of Plm II and improved selectivity over cathepsin D. Hydrogen bonding interaction plays an important role for amino acid residues such as Asp-34, Asp-214, Thr-217, Ser-218, Val-78, Ser-79, Tyr-192 and Gly-216. The binding of the inhibitors to the enzyme, while producing no large distortions in the enzyme active site cleft, results in significant RMS deviations of the inhibitor, which represent the distortion of the inhibitor, effected by the proteinase. Thus, the information generated from this analysis should be useful for further work in the area of antimalarial research.
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PMID:Molecular dynamics simulations of the three dimensional model of plasmepsin II-peptidic inhibitor complexes. 1176 33

Plasmepsin II is a key enzyme in the life cycle of the Plasmodium parasites responsible for malaria, a disease that afflicts more than 300 million individuals annually. Since plasmepsin II inhibition leads to starvation of the parasite, it has been acknowledged as an important target for the development of new antimalarials. In this paper, we identify and characterize high-affinity inhibitors of plasmepsin II based upon the allophenylnorstatine scaffold. The best compound, KNI-727, inhibits plasmepsin II with a K(i) of 70 nM and a 22-fold selectivity with respect to the highly homologous human enzyme cathepsin D. KNI-727 binds to plasmepsin II in a process favored both enthalpically and entropically. At 25 degrees C, the binding enthalpy (DeltaH) is -4.4 kcal/mol and the entropic contribution (-TDeltaS) to the Gibbs energy is -5.56 kcal/mol. Structural stability measurements of plasmepsin II were also utilized to characterize inhibitor binding. High-sensitivity differential scanning calorimetry experiments performed in the absence of inhibitors indicate that, at pH 4.0, plasmepsin II undergoes thermal denaturation at 63.3 degrees C. The structural stability of the enzyme increases with inhibitor concentration in a manner for which the binding energetics of the inhibitor can quantitatively account. The effectiveness of the best compounds in killing the malaria parasite was validated by performing cytotoxicity assays in red blood cells infected with Plasmodium falciparum. EC50s ranging between 6 and 10 microM (3-6 microg/mL) were obtained. These experiments demonstrate the viability of the allophenylnorstatine scaffold in the design of powerful and selective plasmepsin inhibitors.
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PMID:Identification and characterization of allophenylnorstatine-based inhibitors of plasmepsin II, an antimalarial target. 1184 Dec 19

The aspartic proteinases are a family of enzymes involved in a number of important biological processes. In animals the enzyme renin has a hypertensive action through its role in the renin-angiotensin system. The retroviral aspartic proteinases, such as the HIV proteinase, are essential for maturation of the virus particle and inhibitors have a proven therapeutic record in the treatment of AIDS. The lysosomal aspartic proteinase cathepsin D has been implicated in tumorigenesis and the stomach enzyme pepsin, which plays a major physiological role in hydrolysis of acid-denatured proteins, is responsible for much of the tissue damage in peptic ulcer disease. Since aspartic proteinases also play major roles in amyloid disease, malaria and common fungal infections such as candidiasis, inhibitors to these enzymes are much sought after as potential therapeutic agents. In all aspartic proteinases, the catalytic aspartate residues are involved in an intricate arrangement of hydrogen bonds involving a solvent molecule which is presumed to be water. The catalytic mechanism is thought to involve nucleophilic attack of the active site water molecule on the scissile bond carbonyl generating a tetrahedral gem-diol intermediate. The design of inhibitors generally involves the use of short oligopeptides containing a transition state analogue which mimic this tetrahedral intermediate. The application of structure-based drug design to members of the aspartic proteinase family is the main subject of this review.
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PMID:Aspartic proteinases in disease: a structural perspective. 1195 98

A series of malaria plasmepsin (Plm) I and II inhibitors containing a C(2)-symmetric core structure have been synthesised and tested for protease inhibition activity. These compounds can be prepared using a straightforward synthesis involving a phenol nucleophilic ring opening of a diepoxide. Exemplar compounds synthesised exhibited remarkable inhibitory activity against both Plm I and II, notably 15c with K(i) values of 2.7nM and 0.25nM respectively, as well as showing >100-fold selectivity against Cathepsin D.
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PMID:New potent C2-symmetric malaria plasmepsin I and II inhibitors. 1262 51

The last decade has witnessed an effervescence of research interest in the development of potent inhibitors of various aspartic peptidases. As an enzyme family, aspartic peptidases are relatively a small group that has received enormous interest because of their significant roles in human diseases like involvement of renin in hypertension, cathepsin D in metastasis of breast cancer, beta-Secretase in Alzheimer's Disease, plasmepsins in malaria, HIV-1 peptidase in acquired immune deficiency syndrome, and secreted aspartic peptidases in candidal infections. There have been developments on clinically active inhibitors of HIV-1 peptidase, which have been licensed for the treatment of AIDS. The inhibitors of plasmepsins and renin are considered a viable therapeutic strategy for the treatment of malaria and hypertension. Relatively few inhibitors of cathepsin D have been reported, partly because of its uncertain role as a viable target for therapeutic intervention. The beta-secretase inhibitors OM99-2 and OM003 were designed based on the substrate specificity information. The present article is a comprehensive state-of-the-art review describing the aspartic peptidase inhibitors illustrating the recent developments in the area. In addition, the homologies between the reported inhibitor sequences have been analyzed. The understanding of the structure-function relationships of aspartic peptidases and inhibitors will have a direct impact on the design of new inhibitor drugs.
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PMID:Aspartic peptidase inhibitors: implications in drug development. 1274 95


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