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

Proton nuclear magnetic resonance and ultraviolet circular dichroism spectroscopy have been used to probe the conformational ensemble of the tandemly repeating tetrapeptide unit of the circumsporozoite coat protein of the malaria parasite Plasmodium falciparum. Peptides based on the Asn-Ala-Asn-Pro and Asn-Pro-Asn-Ala cadences and composed of one to three tetrapeptide units were synthesized and examined using one- and two-dimensional NMR spectroscopy. The chemical shift of the amide protons, the temperature dependence of the amide proton chemical shift, and the patterns of NOE connectivities in the various peptides give evidence for the presence of a substantial population of folded conformers in several of the peptides in water solution at pH 5.0. Correlations between the behavior of the tandemly repeated units in different peptides have been used to infer the structure(s) of the folded conformers. The data are consistent with the presence of turnlike structures stabilized by hydrogen bonding of the backbone amide protons of the alanines and the asparagine residues preceding them. Specific differences in the strengths of NOEs between peptides of different lengths indicate that the folded structure is considerably stabilized by the presence of the asparagine residue following the alanine. Differences between peptides with different cadences of the tandemly repeating unit indicate that a repeating structural motif is formed by the Asn-Pro-Asn-Ala-(Asn) cadence.
 ...
PMID:Conformational preferences of synthetic peptides derived from the immunodominant site of the circumsporozoite protein of Plasmodium falciparum by 1H NMR. 226 40

10-(4'-Chlorophenyl)-3-methylflavin has antimalarial activity in vitro and in vivo (Cowden et al., J Med Chem 31: 799, 1988). This flavin analog and two of its derivatives were found to inhibit the antioxidant flavoenzyme glutathione reductase from human erythrocytes in its isolated form as well as in hemolysates. The mixed-type inhibition was completely reversible, the Ki-values being of the order of 1 microM. Surprisingly, the drugs were not competitive with FAD, but with GSSG, one of the enzyme's substrates. Malaria parasite glutathione reductase, extracted from Plasmodium falciparum, could also be inhibited by the compounds. Studies on the effects of the substances on P. falciparum in vitro, which were demonstrated morphologically and by growth inhibition, confirmed previous observations with 10-(4'-chlorophenyl)-3-methylflavin and showed similar parasiticidal characteristics for the two new derivatives. The activities of five other erythrocytic enzymes tested were not impaired by the drugs, nor was the nucleotide metabolism of erythrocytes and/or parasites significantly changed. Permeation into red blood cells was demonstrated for one compound by 19F-NMR-spectroscopy. Inhibition of glutathione reductase might contribute to, or account for, the antimalarial activity of this group of flavin analogs.
 ...
PMID:Flavin analogs with antimalarial activity as glutathione reductase inhibitors. 240 94

Arteether (6) has been prepared from dihydroquinghaosu (3) by etherification with ethanol in the presence of Lewis acid and separated from its chromatographically slower moving alpha-dihydroqinghaosu ethyl ether (7). The absolute stereochemistry at C-12 has been determined by 1H NMR data (J11,12, NOESY). Ethyl ethers 6 and 7 showed potent in vitro inhibition of Plasmodium falciparum, and both compounds were highly potent antimalarials in mice infected with a drug-sensitive strain of Plasmodium berghei. Crystalline arteether (6) and its oily epimer 7 were 2-3 times more potent schizontocides than quinghaosu (1), but deoxy compounds 8, 9, and 11 were 100-300 times less potent in vitro than their corresponding peroxy precursors. Pharmacological studies have shown arteether(6) to have antimalarial activity in animals comparable to artesunate (2) and artemether (4), both of which are fast-acting blood schizontocides in humans. Arteether (6) has now been chosen for a clinical evaluation in high-risk malaria patients.
 ...
PMID:Arteether, a new antimalarial drug: synthesis and antimalarial properties. 327 8

The carriage of oxygen by the blood and the in vivo response of the brain were investigated in mice infected with a lethal strain of Plasmodium yoelii. All mice with parasitaemia exceeding 70% were severely anaemic (Hb 3.5 +/- 1.8 g/dl; mean +/- 1 SD), acidotic (blood pH 7.04 +/- 0.06) and hypoglycaemic (blood glucose 0.6 +/- 0.76 mumol/ml). The oxyhaemoglobin dissociation curve (ODC) of blood from heavily infected mice was shifted right as compared to controls, but the increase in p50 was less than expected from the accompanying acidosis. The reduced shift right was due to a decrease in the 2,3-DPG/Hb ratio in infected animals (0.72 +/- 0.12, n = 17 vs 1.10 +/- 0.09, n = 12 in controls). Despite the severity of terminal infection, the cerebral pH and the relative steady-state concentrations of PCr, ATP and Pi measured in vivo by nuclear magnetic resonance (31P NMR) were normal. Alterations in brain energy status and pH cannot account for cerebral signs or death in this proposed mouse model of cerebral malaria.
 ...
PMID:Plasmodium yoelii: blood oxygen and brain function in the infected mouse. 664 96

High resolution 31P-NMR has been used for the non-invasive observation of metabolites and metabolic rates in blood of normal mice and of mice infected with Plasmodium berghei, the causative agent of malaria. 31P-NMR was used to quantitate levels of 2,3-diphosphoglycerate in whole cells as a function of the degree of parasitemia and yielded good agreement with the results of enzymatic assays. The time-dependence of 31P metabolites was monitored in both normal and infected erythrocytes, greater rates of decay of 2,3-diphosphoglycerate being observed in malarial blood which correlate with the level of parasitemia. Very high metabolic rates of infected cells render measurement of intracellular pH unreliable on freshly drawn whole blood. When appropriate measures are taken to avoid this complication, no difference is observed in the intracellular pH of parasitized and non-parasitized erythrocytes from infected animals. In both normal and parasitized mice the intraerythrocytic pH is more acidic than that of the suspending medium by 0.15 pH unit at 25 degrees C. Unlike free-living protozoa, the parasitic protozoan Plasmodium does not contain detectable levels of phosphonates or polyphosphates, in either whole cells or perchloric acid extracts thereof.
 ...
PMID:NMR studies of malaria. 31P nuclear magnetic resonance of blood from mice infected with Plasmodium berghei. 676 Sep 1

The effects of 1-stearoyl,2-sn-arachidonoylglycerol (SAG) and the antimalarial drug chloroquine on lipid bilayer structure were studied by 2H-NMR spectroscopy. Model lipid systems were established with compositions similar to those of normal human erythrocytes, malaria-infected erythrocytes, or malaria parasite membranes. The 2H-NMR spectra of the membranes formed from the lipids extracted from normal human erythrocytes were similar to those obtained using the corresponding lipid mixtures. The order parameters of the model "infected" and model "parasite" membranes were reduced markedly relative to that of normal erythrocytes. Addition of SAG induced formation of non-bilayer lipid phases in all lipid systems. Only a small decrease in the order parameters of the acyl side chains of the phosphatidylserine, but not of the phosphatidylcholine component of the lipid membranes, was observed upon the addition of chloroquine. A dramatic effect was observed upon the addition of chloroquine to the SAG-containing membranes: this antimalarial almost totally abolished the formation of SAG-induced non-bilayer lipid phases. Since SAG, endogenously formed in erythrocyte membranes, is a potent activator of phospholipase A2, this membrane-stabilizing action of chloroquine may partially account for the phospholipase A2-inhibiting properties of this drug, and, consequently, for both its therapeutic and toxic modes of action.
 ...
PMID:Chloroquine stabilization of phospholipid membranes against diacylglycerol-induced perturbation. 842 11

Cholestane-derived gem-dihydroperoxides and tetraoxanes were synthesized starting from 5 alpha- and 5 beta-cholestan-3-ones by acid-catalyzed addition of hydrogen peroxide to the ketone. They were characterized by IR, NMR, and mass spectroscopy analysis aided by molecular mechanics calculations, and, in the instance of 5 beta-cholestane-3 alpha,3 beta-dihydroperoxide (6), by x-ray analysis. The synthesized compounds were tested in vitro against Plasmodium falciparum Sierra Leone (D6) and Indochina (W2) malaria clones. All compounds were inactive to both clones, with the exception of tetraoxane 7a, which exhibited modest activity toward D6 clone with IC50 = 155 nM.
 ...
PMID:Steroidal geminal dihydroperoxides and 1,2,4,5-tetraoxanes: structure determination and their antimalarial activity. 898 37

The immunodominant region on the circumsporozoite surface (CS) protein of the malaria parasite Plasmodium falciparum contains 37 repeated copies of a asparagine-alanine-asparagine-proline (NANP) motif NMR studies of linear synthetic peptides containing one, two or three repeat units provided evidence for nascent type I beta-turns within the NPNA cadence in aqueous solution. The beta-turns could be stabilised upon substituting proline for alpha-methylproline (p(Me)) in the dodecamer (NP(Me)NA)3, without loss of the ability to elicit antibodies cross-reactive with P. falciparum sporozoites. In this work, four 4 ns MD simulations of the dodecapeptide Acetyl-(NP(Me)NA)3, in water, using NOE distance restraints, using 3J-coupling constant restraints, using both these restraints and without restraints, were carried out to determine the conformations of this peptide in aqueous solution. An unrestrained MD simulation of the unmethylated Ac-(NPNA)3 peptide in water was also carried out to investigate the effect of the additional methyl groups on the structure and dynamics of the peptide. The application of NOE distance restraints and 3J-coupling constant restraints leads to contradictory results, probably due to different averaging time scales inherent to the measurement of these data, which exceed the 100 ps averaging applied in the simulations. The additional methyl groups lead to more compact structures, which display enhanced local fluctuations. The central tetrapeptide adopts a type I beta-turn, while the outer motifs display more conformational variability. The three motifs in the methylated dodecamer peptide, however, adopt frequently in the distance restrained MD simulation a compact structure such that the outer motifs appear to form a hydrophobic core by stacking of their two proline rings. This arrangement also suggests how a peptide containing multiple tandemly linked copies of a stable beta-turn NPNA motif might adopt a folded stem-like structure, which conceivably may be of biological relevance in the native CS protein.
 ...
PMID:Dynamical studies of peptide motifs in the Plasmodium falciparum circumsporozoite surface protein by restrained and unrestrained MD simulations. 913 27

Two antiprotozoal compounds have been isolated from the roots of Asparagus africanus Lam. (Liliaceae), a new sapogenin, 2 beta, 12 alpha-dihydroxy-(25R)-spirosta-4,7-dien-3-one (1), which was named muzanzagenin, and the lignan (+)-nyasol (2), (Z)-(+)-4,4'-(3-ethenyl-1-propene-1,3-diyl)-bisphenol. The structure of the sapogenin was elucidated by MS and by 1D and 2D NMR methods and established by a single crystal X-ray analysis. (+)-Nyasol potently inhibits the growth of Leishmania major promastigotes, the IC50 being 12 microM, and moderately inhibits Plasmodium falciparum schizonts with the IC50 49 microM. These concentrations only moderately affect the proliferation of human lymphocytes. Muzanzagenin showed a moderate in vitro activity in all three tests, the IC50 against leishmania promastigotes was 70 microM, and against four different malaria schizont strains the IC50 values were 16, 163, 23, and 16 microM, respectively.
 ...
PMID:Antiprotozoal compounds from Asparagus africanus. 935 45

A psi[CH2NH] isoster bond was introduced by replacing one peptide bond at a time within the 1513 malaria peptide KEKMV motif to obtain a set of five pseudopeptides. The motif belongs to a Plasmodium falciparum malarial peptide coded 1513, derived from the MSP-1 protein. This high-binding motif included in the 1513 peptide is involved in the attachment of the malarial parasite to human erythrocytes. The novel malaria 1513 psi[CH2NH] surrogates were analyzed using RP-HPLC and MALDI-TOF mass spectrometry techniques. Nuclear magnetic resonance experiments allowed definition of the five pseudopeptide analogues' secondary structural features. Such structures are present in only a very few molecules in the 1513 parent peptide. A molecular model demonstrating the solution of the three-dimensional structure of the 1 513 peptide Pse-437 analogue was constructed on the basis of 1H-NMR spectral parameters. Monoclonal antibodies were generated to the five 1513 malaria peptide pseudopeptide analogues. These antibodies not only recognize the native MSP-1 (195 kDa) and its 83 kDa and 42 kDa proteolytic processing proteins but also different SPf(66)n malaria vaccine batches containing the native sequence. In addition, the mAbs were able to modify the kinetics of Plasmodium falciparum parasites' intraerythrocytic development and their ability to invade new RBCs. The presented evidence suggests that peptide bond-modified peptides could reproduce a transient state in 1513's native sequence and represent useful candidates in the development of a second generation of effective malarial vaccines.
 ...
PMID:Reduced amide pseudopeptide analogues of a malaria peptide possess secondary structural elements responsible for induction of functional antibodies which react with native proteins expressed in Plasmodium falciparum erythrocyte stages. 992 90


1 2 3 4 5 6 7 8 9 10 Next >>