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)

Linear B- and T-cell epitopes have been identified in the Plasmodium falciparum clustered-asparagine-rich-protein (CARP). Twenty-six synthetic peptides, 15-25 amino acids in length, were assayed for their ability to stimulate purified, human T-cells primed to P.falciparum by natural infection to proliferate and/or secrete gamma-interferon (IFN gamma). The plasma of malaria exposed individuals were tested for antibody reactivity with peptides coupled to bovine serum albumin in a semiquantitative ELISA. Two of the peptides (NNFMNRNMKNKNMN/NAKNVNDMYRDGEMS) induced T-cells from many malaria exposed donors to proliferate and/or secrete-IFN gamma. Six peptides bound antibodies from a large number of the plasma samples, the amounts ranging from ten to more than 200 micrograms specific antibody/ml. T-cell activation was most pronounced when the T-cells were from highly immune donors. In contrast, high anti-peptide specific antibody levels were usually detected in the plasma of less immune donors, recently exposed to infection. One short sequence (NAKNVNDMYRDGEMS) was found to contain both T- and B-cell epitopes. Thus, CARP includes both T- and B-cell reactive elements recognized by the human immune system following exposure to the parasite by natural infection.
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PMID:Epitopes of the Plasmodium falciparum clustered-asparagine-rich protein (CARP) recognized by human T-cells and antibodies. 172 21

The effectiveness of synthetic vaccines is dependent upon the chance event that antibodies formed against largely disordered peptides can bind native protein surfaces which are often ordered. To improve on this situation, new methods are being developed for the conformational restriction of synthetic peptides. Cognate peptide sequences often form predictable secondary structures in proteins characterized by distinct hydrogen-bonding patterns. These weak hydrogen bonds have now been replaced with covalent mimics to conformationally restrict selected peptides to the Type 1 reverse turn and alpha helix. Potential uses for this chemistry are discussed in the context of malaria vaccines. The peptide component of a Plasmodium falciparum sporozoite vaccine, acetyl-(ASN-ALA-ASN-PRO)3-NH2 has been conformationally analysed using two-dimensional nuclear magnetic resonance spectroscopy. These studies are consistent with the formation of transiently ordered turnlike structures which provide a guide for the design and synthesis of a conformationally restricted synthetic vaccine. To assess the effects of conformational restriction and chemical modification on the sporozoite vaccine, ASN side-chains were linked around proline with ethylene bridges. Polyclonal antibodies to this shaped peptide show a strong cross-reaction with living sporozoites.
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PMID:The conformational restriction of synthetic vaccines for malaria. 209 82

Members of the RNA-binding protein superfamily contain RNA binding domains of about 90 amino acids with a highly conserved motif 'GFGF'. Using the conserved motif with some variations G-(F/Y)-(G/A)-(F/Y)-(V/I)-X-(F/Y) as a probe, we screened protein sequences carrying identical amino acids in an NBRF-protein database. It has been found that the C-terminal portion of clustered asparagine-rich protein (CARP), a malaria antigen from Plasmodium falciparum, shows an unexpected sequence similarity with the RNA-binding protein superfamily for the C-terminal half of the RNA-binding domain. Dot matrix comparisons and alignment of these sequences as well as a statistical test have revealed highly significant sequence similarities. From these analyses, we conclude that the malaria antigen CARP belongs to a large family of the RNA-binding proteins. An evolutionary implication of the sequence similarity was also discussed.
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PMID:RNA-binding protein-related sequence in a malaria antigen, clustered-asparagine-rich protein. 210 36

Selection of the rodent malaria Plasmodium chabaudi with low levels of the antifolate drug pyrimethamine has previously been shown by us to result in duplication of the dihydrofolate reductase-thymidylate synthase (DHFR-TS) gene by a duplication of chromosome 7 and subsequent rearrangements. We have selected this resultant parasite line with large doses of pyrimethamine and analysed the DHFR-TS gene and chromosomes for any changes. Increased drug pressure has resulted in reappearance of a chromosome with the same structure as chromosome 7 from DS the parent line. Sequencing of the DHFR gene from each of the chromosomes has identified a single point mutation that results in a serine to asparagine change at position 106. This is the equivalent mutation that has been identified as the key residue in the mechanism of resistance to pyrimethamine in Plasmodium falciparum. There is no apparent increase in transcription of the DHFR-TS gene and the large increase in resistance is most likely a result of the mutation in the DHFR gene.
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PMID:Chromosomal rearrangements and point mutations in the DHFR-TS gene of Plasmodium chabaudi under antifolate selection. 223 98

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.
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PMID:Conformational preferences of synthetic peptides derived from the immunodominant site of the circumsporozoite protein of Plasmodium falciparum by 1H NMR. 226 40

We describe a cDNA clone derived from mRNA of asexual blood-stages of the malaria parasite Plasmodium falciparum. This clone, designated Ag319, expresses a P.falciparum antigen fused to beta-galactosidase in Escherichia coli. Human antibodies from Papua New Guinea were affinity-purified by adsorption to extracts of Ag319 immobilized on CNBr-Sepharose. The antibodies reacted predominantly with P. falciparum polypeptides of Mr 220,000 and 160,000, and a number of ill-defined lower molecular weight species. Antibodies reacted in indirect immunofluorescence with all asexual blood-stages although the antigen appeared to be most abundance in the schizont. Surprizingly the antibodies also reacted with sporozoites. The amino acid sequence predicted from the complete nucleotide sequence of this clone is remarkable because 40% of the residues are Asn, and so the antigen has been termed the Asparagine-Rich Protein (ARP). Like other P. falciparum antigens, ARP contains tandemly repetitive sequences, based on the tetrapeptide Asn-Asn-Asn-Met and we have confirmed that these represent natural epitopes by reaction of the corresponding synthetic peptides with human antibodies. Surprisingly, ARP is also rich in Asn outside the tandem repeats.
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PMID:An asparagine-rich protein from blood stages of Plasmodium falciparum shares determinants with sporozoites. 242 Dec 57

Malaria continues to cause extensive morbidity and mortality in man. The exact number of individuals affected is not known. Estimates vary from 200 to 400 million, and more than one million die each year. Protective immunity against malaria can be obtained by vaccination with irradiated sporozoites. The protective antigens are polypeptides (circumsporozoite [CS] proteins) which cover the surface membrane of the parasite. CS proteins contain species-specific immunodominant epitopes, formed by tandem repeated sequences of amino acids. The dominant epitope of Plasmodium falciparum is represented in the synthetic peptide asparagine-alanine-asparagine-proline repeated in tandem three times; that is, (NANP)3. Monoclonal antibodies and most or all polyclonal human antibodies to P. falciparum sporozoites react with (NANP)3. Polyclonal antibodies raised against the synthetic peptide (NANP)3 react with the surface of the parasite and neutralize its infectivity. Since (NANP)3 repeats are present worldwide in CS proteins from P. falciparum, this epitope is a logical target for vaccine development.
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PMID:Experimental basis for the development of a synthetic vaccine against Plasmodium falciparum malaria sporozoites. 242 50

A clone encoding a recombinant protein which reacted strongly with human antibodies from a donor clinically immune to malaria, was isolated from a genomic Plasmodium falciparum library. Mice injected with this protein, designated 10b, produced antibodies which reacted with all developmental stages of erythrocytic asexual parasites in indirect immunofluorescence. In immunoblotting, the same antibodies recognized two P. falciparum polypeptides of 36 kDa and 33 kDa. Of three monoclonal antibodies raised against the 10b recombinant protein, two inhibited parasite reinvasion of erythrocytes in an isolate specific manner. Surprisingly, however, the third was found to significantly enhance reinvasion of erythrocytes and also to induce a more rapid maturation of intraerythrocytic parasites in all isolates tested. Nucleotide sequence analysis of the 1124 bp insert revealed that it encodes a protein which consists of 30% asparagine and contains three asparagine rich, imperfect tandem repeats: Lys-Lys-Asn-Asn (3x), Met-Asn-His/Gln-Pro-Asn-Asn (14x), and Lys-Asn-Asn-Asn-Asn (7x).
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PMID:Enhancement or inhibition of Plasmodium falciparum erythrocyte reinvasion in vitro by antibodies to an asparagine rich protein. 246 5

A major sporozoite surface antigen, the circumsporozoite protein, has been identified in all four malaria parasites affecting humans and in numerous species causing malaria in rodents and simians. The corresponding genes have been cloned and sequenced, and considerable similarities are apparent. An extensive central region of these proteins consists of tandemly repeated sequences of four to 16 amino acids. The sporozoite protein of Plasmodium falciparum has 37-41 repeats of four amino acids: NANP (asparagine-alanine-asparagine-proline). Most sera from people in endemic areas that react with sporozoites also recognize the dodecamer (NANP)3. Conjugated to a carrier, (NANP)3 is an excellent immunogen for rabbits and mice. NANP has recently served as the basis for two experimental malaria vaccines tested in volunteers. One of these vaccines, (NANP)32 tet32, was genetically engineered in Escherichia coli; the other consisted of the synthetic peptide (NANP)3 conjugated to tetanus toxoid. Most peptide-immunized volunteers developed antipeptide/sporozoite antibodies; however, there was no booster effect, and only one of three individuals was completely protected. For optimal protection, future vaccines must not only contain the B cell epitope but also induce T helper cells and cytotoxic T cells producing interferon-gamma, which has been shown to inhibit the development of liver-stage parasites.
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PMID:Antisporozoite vaccine for malaria: experimental basis and current status. 266 1

A new strategy for designing synthetic vaccines is presented. In this approach synthetic peptides are conformationally restricted by replacing putative hydrogen bonds with covalent mimics. The chemistry for substituting a hydrazone-ethane link (N-N = CH-CH2-CH2) for an (i + 4)----i hydrogen bond in a pentapeptide with alpha-helical potential is reported. Chemically shaping peptides to mimic the three-dimensional surfaces of proteins may enhance their immunogenicity. To test this strategy, a potential synthetic vaccine for malaria, Cys-(Asn-Pro-Asn-Ala)3-NH2, was conformationally restricted by replacing putative hydrogen bonds between asparagine side chains with a covalent replacement, an ethylene bridge, to give first generation chemically shaped immunogens. Antibodies to one of the shaped malarial peptides show a strong reaction with living Plasmodium falciparum sporozoites, a form of malaria which infects hundreds of millions of people yearly.
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PMID:Conformational restriction of peptidyl immunogens with covalent replacements for the hydrogen bond. 329 60


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