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)

A pathophysiologic study was made in 15 patients with acute renal failure due to falciparum malaria. Marked increase in plasma fibrinogen and elevation of serum fibrin degradation products were observed in all cases. The other coagulation parameters including prothrombin time, partial thromboplastin time, factor V and factor VIII were within the normal limits. Plasma hemoglobin was minimal. The blood viscosity was significantly increased. Blood volume study in 5 patients showed initial hypovolemia followed by hypervolemia and normovolemia. Decreased cortical renal blood flow was noted in renal hemodynamic study using 133Xe. Plasma renin activity was increased. Intravenous pyelography during the oliguric phase of renal failure revealed a poor nephrogram which increased in density at 24 and 48 h after the injection of the contrast material. The findings suggest the significance of reduction of renal blood flow in the pathogenesis of renal failure in human malaria. The roles of blood hyperviscosity and hypovolemia are emphasized.
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PMID:Renal failure in malaria: a pathophysiologic study. 86 56

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

Prolyl oligopeptidase (EC 3.4.21.26) activity was measured in human tissue homogenates and body fluids. The enzyme was ubiquitously present, revealing high activity in renal cortex, epithelial cells, fibroblasts, testis, lymphocytes and thrombocytes. The activity in the body fluids was low. Prolyl oligopeptidase activity was significant higher in tumours of prostate, lung and sigmoid, than in the healthy tissues. Sera of individuals suffering from HIV infection, malaria, prostate cancer or benign prostate hypertrophy contained lowered activity. Interestingly, the low serum activity during prostate carcinoma increased upon medical treatment with anti-androgens. This suggests hormonal control of the gene transcript. A positive correlation with angiotensin converting enzyme activity in hypertensive patients was demonstrated and this further supports the possible involvement of prolyl oligopeptidase in the renin-angiotensin system and in the pathogenesis of hypertension.
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PMID:Distribution of prolyl oligopeptidase in human peripheral tissues and body fluids. 870 29

Renal and systemic hemodynamics, plasma arginine vasopressin, plasma renin activity, plasma norepinephrine, blood volume and water loading test were studied in 10 patients with falciparum malaria without renal failure. Six patients responded to water load normally, while 4 patients had a decreased response to water load. The patients with a normal water load response had normal renal and systemic hemodynamics and a normal hormonal profile. The patients with a decreased response to water load had hyponatremia, hypervolemia, high cardiac index, low systemic vascular resistance, high plasma arginine vasopressin, high plasma renin activity, high plasma norepinephrine, low creatinine and p-aminohippurate clearances, low urine sodium and high urine osmolality. They had a lower mean arterial pressure during the acute phase of the disease than during the recovery phase. The findings suggest that a decreased response to water load is due to peripheral vasodilatation which results in a decreased effective blood volume leading to the release of vasopressin and norepinephrine, increased renin activity and decreased renal hemodynamics.
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PMID:Renal and systemic hemodynamics, in falciparum malaria. 895 63

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

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

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

Severe malaria has been, in part, associated with the ability of parasite infected red blood cells to aggregate together with uninfected erythrocytes to form rosettes via the parasite protein PfEMP-1. In this study, inhibitors of rosetting by the Plasmodium falciparum strain R-29, based on chemically modified heparin polysaccharides (IC 50 = 1.97 x 10 (-2) and 3.05 x 10 (-3) mg.mL (-1)) and their depolymerized, low molecular weight derivatives were identified with reduced anticoagulant and protease (renin, pepsin, and cathepsin-D) activities. Low molecular weight derivatives of the two most effective inhibitors were shown to have distinct minimum size and strain-specific structural requirements for rosette disruption. These also formed distinct complexes in solution when bound to platelet-factor IV.
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PMID:Disruption of rosetting in Plasmodium falciparum malaria with chemically modified heparin and low molecular weight derivatives possessing reduced anticoagulant and other serine protease inhibition activities. 1826 Jun 12

In this retrospective, personal review covering our research from the late 1980s until 2007, we outline nearly two-decade worth of our own work on several aspartic protease inhibitors including those affecting renin, HIV-1 protease, plasmepsins, beta-secretase, and HTLV-I protease and we report on aspartic protease inhibitors as potential drugs to treat hypertension, AIDS, malaria, Alzheimer's disease and adult T-cell leukemia, HTLV-I associated myelopathy / tropical spastic paraparesis, and various, respectively, associated diseases. Herein, we describe our methods for rational substrate-based drug design of peptidomimetics that potently inhibit the activity of renin, HIV-1 protease, plasmepsins, beta-secretase, and HTLV-I protease accordingly, using an appropriately selected inhibitory residue that contained a hydroxymethylcarbonyl isostere. Although this non-hydrolyzable isostere mimics the transition state that is formed during protein cleavage of a substrate, the isostere-containing inhibitor is not cleaved. We highlight our optimization studies in which we used various techniques and tools such as truncation studies, natural and non-natural amino acid substitution studies, various moieties to promote chemical and pharmacological stability, X-ray crystallography, computer-assisted docking and dynamic simulations, quantitative structure-activity relationship studies, and various other methods that this review can barely mention.
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PMID:Design of potent aspartic protease inhibitors to treat various diseases. 1876 14

Plasmodium falciparum causes the most serious complications of malaria and is a public health problem worldwide with over 2 million deaths each year. The erythrocyte invasion mechanisms by Plasmodium sp. have been well described, however the physiological aspects involving host components in this process are still poorly understood. Here, we provide evidence for the role of renin-angiotensin system (RAS) components in reducing erythrocyte invasion by P. falciparum. Angiotensin II (Ang II) reduced erythrocyte invasion in an enriched schizont culture of P. falciparum in a dose-dependent manner. Using mass spectroscopy, we showed that Ang II was metabolized by erythrocytes to Ang IV and Ang-(1-7). Parasite infection decreased Ang-(1-7) and completely abolished Ang IV formation. Similar to Ang II, Ang-(1-7) decreased the level of infection in an A779 (specific antagonist of Ang-(1-7) receptor, MAS)-sensitive manner. 10(-7) M PD123319, an AT(2) receptor antagonist, partially reversed the effects of Ang-(1-7) and Ang II. However, 10(-6) M losartan, an antagonist of the AT(1) receptor, had no effect. Gs protein is a crucial player in the Plasmodium falciparum blood cycle and angiotensin peptides can modulate protein kinase A (PKA) activity; 10(-8) M Ang II or 10(-8) M Ang-(1-7) inhibited this activity in erythrocytes by 60% and this effect was reversed by 10(-7) M A779. 10(-6) M dibutyryl-cAMP increased the level of infection and 10(-7) M PKA inhibitor decreased the level of infection by 30%. These results indicate that the effect of Ang-(1-7) on P. falciparum blood stage involves a MAS-mediated PKA inhibition. Our results indicate a crucial role for Ang II conversion into Ang-(1-7) in controlling the erythrocytic cycle of the malaria parasite, adding new functions to peptides initially described to be involved in the regulation of vascular tonus.
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PMID:Impairment of the Plasmodium falciparum erythrocytic cycle induced by angiotensin peptides. 2136 58


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