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)

Peptide vaccines based on units of the immunodominant tetrapeptide repeats, Asn-Ala-Asn-Pro and Asn-Val-Asp-Pro, of the circumsporozoite surface protein of the parasite Plasmodium falciparum are presently being developed as potential malaria vaccines. The N-terminal fusion of a hydrophobic protein to units of the tetrapeptide repeat affected the immunogenicity and conformational stability of the peptide, and also induced a secondary structure in the peptide. Peptide antigenicity, as well as conformational stability, was significantly increased.
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PMID:Conformation and immunogenicity of engineered repeating segment of the circumsporozoite surface protein of Plasmodium falciparum. 218 2

Proguanil and pyrimethamine are antifolate drugs with distinct chemical structures that are used commonly in the prophylaxis and treatment of Plasmodium falciparum malaria. Clinical reports and field studies have suggested that some parasites refractory to proguanil can be treated with pyrimethamine, and vice versa. Analysis of the P. falciparum dihydrofolate reductase (DHFR) from different parasites reveals the structural basis for differential susceptibility to these antifolate drugs. Parasites harboring a pair of point mutations from Ala-16 to Val-16 and from Ser-108 to Thr-108 are resistant to cycloguanil (the active metabolite of proguanil) but not to pyrimethamine. A single Asn-108 mutation, on the other hand, confers resistance to pyrimethamine with only a moderate decrease in susceptibility to cycloguanil. Significant cross-resistance to both drugs occurs in parasites having mutations that include Ser-108----Asn-108 and Ile-164----Leu-164. These results reflect the distinct structures of pyrimethamine and cycloguanil and suggest fine differences in binding within the active site cavity of DHFR. Alternative inhibitors, used alone or in combination, may be effective against some strains of cycloguanil- or pyrimethamine-resistant malaria.
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PMID:Molecular basis of differential resistance to cycloguanil and pyrimethamine in Plasmodium falciparum malaria. 218 22

Protective immunity against malaria can be obtained by vaccination with irradiated sporozoites. The protective antigens known as circumsporozoite (CS) proteins, are polypeptides that cover the surface membrane of the parasite. The CS proteins contain species-specific immunodominant epitopes formed by tandem repeated sequences of amino acids. Here it is shown that the dominant epitope of Plasmodium falciparum is contained in the synthetic dodecapeptide Asn-Ala-Asn-Pro-Asn-Ala-Asn-Pro-Asn-Ala-Pro or (NANP)3. Monoclonal antibodies and most or all polyclonal human antibodies to the sporozoites react with (NANP)3, and 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 in CS proteins of P. falciparum from many parts of the world, this epitope is a logical target for vaccine development.
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PMID:Rationale for development of a synthetic vaccine against Plasmodium falciparum malaria. 240 95

The Plasmodium falciparum-derived antigen of Mr 155,000 designated Pf 155, deposited in the membrane of infected erythrocytes, contains at least two blocks of tandemly repeated amino acid sequences. The peptide Glu-Glu-Asn-Val-Glu-His-Asp-Ala, which corresponds to a subunit of a C-terminally located repeat, was synthesized. Rabbits immunized with the octapeptide conjugated with either keyhole limpet hemocyanine or tetanus toxoid formed antibodies against the octapeptide. These antibodies reacted with Pf 155 as detected by immunoblotting or a modified immunofluorescence assay. Sera from humans exposed to P. falciparum also contained antibodies binding to the octapeptide in a dot-blot immunoassay. Their anti-octapeptide titers were correlated with their immunofluorescence titers in the assay detecting Pf 155 and other parasite antigens in the membrane of infected erythrocytes. Human octapeptide-reactive antibodies were isolated on an affinity column with the octapeptide conjugated to bovine serum albumin as ligand. These human antibodies reacted with Pf 155 in immunoblotting and strongly stained the surface of infected erythrocytes in the modified immunofluorescence assay. Approximately 20% of this immunofluorescence activity in a high-titered human serum could be recovered from the octapeptide column, indicating that a significant fraction of these anti-parasite antibodies react with epitopes associated with the octapeptide. Furthermore, the human octapeptide-reactive antibodies very efficiently inhibited merozoite reinvasion into erythrocytes in vitro. Similarly purified rabbit antibodies also significantly inhibited reinvasion. Our results suggest that the C-terminal segment of repeated peptides in Pf 155 is a major antigenic region of the molecule and may contain target sites for protective immunity in P. falciparum malaria.
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PMID:Rabbit and human antibodies to a repeated amino acid sequence of a Plasmodium falciparum antigen, Pf 155, react with the native protein and inhibit merozoite invasion. 241 97

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

The circumsporozoite protein of the human malaria parasite Plasmodium falciparum contains multiple tandem repeats of the amino acid sequence Asn-Ala-Asn-Pro. The repeated sequence encompasses the immunodominant region of the protein, and antibodies raised against it are potent inhibitors of invasion and development of sporozoites in cultured hepatocytes. Using a modified build-up procedure, we have explored a large number of possible helical and near-helical conformations of a terminally blocked tetraicosapeptide, consisting of six repeats of the sequence Asn-Ala-Asn-Pro, and conclude that two helical conformations are energetically favored to the exclusion of all others. One of these conformations is longer, thinner, and left-handed and is likely to be adopted in nonpolar environments, while the other is shorter, broader, and right-handed and should be favored in aqueous solutions. We propose that the immunodominant region of the circumsporozoite protein of P. falciparum adopts one of these conformations in vivo.
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PMID:Predicted conformations for the immunodominant region of the circumsporozoite protein of the human malaria parasite Plasmodium falciparum. 242 2

A large peptide consisting of about 40 (Asn-Ala-Asn-Pro) repeats of Plasmodium falciparum circumsporozoite protein, (NANP)40, was synthesized. It was recognized specifically by monoclonal antibodies produced against P. falciparum sporozoites. Moreover, this peptide strongly inhibited the binding of such monoclonal antibodies to antigens present in a sporozoite extract. The (NANP)40 peptide was employed without any carrier to develop an enzyme-linked immunosorbent assay to detect sporozoite-specific serum antibodies arising after natural malaria infections. Antibodies were detected in a high percentage (43.1%) of European patients suffering from acute P. falciparum malaria and in Africans living in an area of Gabon endemic for malaria. In the latter group, the frequency of antisporozoite antibodies increased with age, reaching 65.9% in individuals more than 40 years old. There was a significant correlation between the results obtained with an immunofluorescence assay with glutaraldehyde-fixed sporozoites and those obtained by enzyme-linked immunosorbent assay with (NANP)40. Therefore, such synthetic peptides representing the repetitive epitope of P. falciparum circumsporozoite protein can be used for the detection of antisporozoite antibodies and for the epidemiological studies required to obtain base-line data concerning the immune status of individuals before their participation in a sporozoite vaccine trial.
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PMID:Detection of human antibodies against Plasmodium falciparum sporozoites using synthetic peptides. 243 83

An ELISA employing a novel synthetic peptide consisting of 40 (Asn-Ala-Asn-Pro) repeats of Plasmodium falciparum circumsporozoite protein, (NANP)40, was used to detect antibodies against P. falciparum circumsporozoite protein in 132 children, 1 month to 15 years old, from a rural community (Kikwawila village) of Tanzania, a region where malaria is hyperendemic. The children were surveyed comprehensively over 3 consecutive years for clinical, parasitological, and serological parameters. Entomological data were also gathered for selected households in this village. The following results were obtained: anti-(NANP)40 antibodies increased as a function of age; the majority of children over 10 years showed a stable positivity for such antibodies during the longitudinal study; a negative correlation was observed between the levels of anti-sporozoite antibodies and both spleen enlargement and the presence of parasites in thick smears; no relationship was found between anti-(NANP)40 antibodies and asexual blood stage antibodies; children living in two representative households with comparable indoor resting mosquito densities showed markedly different frequencies of anti-(NANP)40 antibodies, in spite of comparable clinical, parasitological, and serological parameters. Thus, in addition to the exposure to infectious mosquito bites, other (e.g., genetic) factors, may play a role in the ability of certain individuals to mount an antibody response against this immunodominant repetitive epitope. The results presented in this paper confirm that the (NANP)40-ELISA represents a simple, reliable means for the detection of anti-(NANP)40 circumsporozoite protein antibodies and suggest that such antibodies may contribute to the immune protection against malaria in humans.
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PMID:Antibodies to the repetitive epitope of Plasmodium falciparum circumsporozoite protein in a rural Tanzanian community: a longitudinal study of 132 children. 243 81

An enzyme-linked immunosorbent assay (ELISA) was developed to detect antibody in human sera to a synthetic peptide, Asn-Ala-Asn-Pro (NANP)3, derived from the repeating amino acid sequence found in the surface circumsporozoite protein of Plasmodium falciparum sporozoites. One hundred four sera from U.S. residents were used to determine a cut-off value for reactivity. Test sera were considered reactive when the absorbance was greater than that at the 95th percentile of the control sera. Sera from 112 Kenyans living in an area of holoendemic malaria transmission were tested. Of the total number of sera, 65% had detectable antibody to (NANP)3. The percentage of reactive sera increased from 41% in sera from children under 4 years of age to 85% in sera from adults 20 to 39 years of age. The high exposure to malaria parasites of the Kenyans was reflected in indirect fluorescent antibody assay titers to blood stage P. falciparum parasites. All of the Kenyan sera had antibody present at titers greater than 1:256.
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PMID:Detection of antibodies in human sera to the repeating epitope of the circumsporozoite protein of Plasmodium falciparum using the synthetic peptide (NANP)3 in an enzyme-linked immunosorbent assay (ELISA). 244 Mar 27

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


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