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)

Three new manzamine-type alkaloids, 12,34-oxamanzamine E (3), 8-hydroxymanzamine J (4), and 6-hydroxymanzamine E (8), as well as 12 previously characterized manzamine alkaloids have been isolated from a common Indonesian sponge of the genus Acanthostrongylophora. The structures of the new compounds have been established on the basis of 1D and 2D NMR spectroscopic analysis and comparison of the data to literature values of related compounds. The biological activities and structure-activity relationship of the manzamines against malaria, Mycobacterium tuberculosis, Leishmania, HIV-1, and AIDS opportunistic infections are discussed. A plausible pathway for the formation of the 12,34-oxaether bridge in compound 3 is also provided.
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PMID:Three new manzamine alkaloids from a common Indonesian sponge and their activity against infectious and tropical parasitic diseases. 1533 48

Conserved, high-activity, red blood cell binding malaria peptide 6786, from the HRP-I protein, having a random 3D structure as determined by 1H-NMR, was non-immunogenic and non-protection inducing when used as an immunogen in Aotus monkeys. Modifications made in its amino acid sequence were thus performed to render it immunogenic and protection inducing. Non-immunogenic, non-protection inducing modified peptide 13852 presented A2-H8 and K14-L18 helix fragments. Immunogenic, non-protection inducing modified peptide 23428 presented a short, displaced helix in a different region, whilst immunogenic, protection inducing peptide 24224 had 2 displaced helical regions towards the central region giving more flexibility to its N- and C-terminals. Immunogenic and protection inducing peptides bound with high affinity to HLA-DRB1* 0301 whilst others did not bind to any HLA-DRB1* purified molecule. Structural modifications may thus lead to inducing immunogenicity and protection associated with their capacity to bind specifically to purified HLA-DRB1* molecules, suggesting a new way of developing multi-component, subunit-based malarial vaccines.
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PMID:Fitting modified HRP-I peptide analogue 3D structure into HLA-DR molecules induces protection against Plasmodium falciparum malaria. 1547 79

Plasmodium falciparum merozoite surface protein 1 (MSP1)(19), the C-terminal fragment of merozoite surface protein 1, is a leading candidate antigen for development of a vaccine against the blood stages of the malaria parasite. Many human and animal studies have indicated the importance of MSP1(19)-specific immune responses. Anti-MSP1(19) antibodies can prevent invasion of red blood cells by P. falciparum parasites in vitro. However, the fine specificity of anti-MSP1(19) antibodies is also important, as only a fraction of monoclonal antibodies (mAbs) have parasite-inhibitory activity in vitro. Human sera from malaria-endemic locations show strong MSP1(19) reactivity, but individual serum samples vary greatly in inhibitory activity. NMR is an excellent method for studying protein-protein interactions, and has been used widely to study binding of peptides representing known epitopes (as well as non-protein antigens) to antibodies and antibody fragments. The recent development of transverse relaxation optimized spectroscopy (TROSY) and related methods has significantly extended the maximum size limit of molecules that can be studied by NMR. TROSY NMR experiments produce high quality spectra of Fab complexes that allow the mapping of epitopes by the chemical shift perturbation technique on a complete, folded protein antigen such as MSP1(19). We studied the complexes of P. falciparum MSP1(19) with Fab fragments from three monoclonal antibodies. Two of these antibodies have parasite-inhibitory activity in vitro, while the third is non-inhibitory. NMR epitope mapping showed a close relationship between binding sites for the two inhibitory antibodies, distinct from the location of the non-inhibitory antibody. Together with a previously published crystal structure of the P. falciparum MSP1(19) complex with the Fab fragment of another non-inhibitory antibody, these results revealed a surface on MSP1(19) where inhibitory antibodies bind. This information will be useful in evaluating the anti-MSP1(19) immune response in natural populations from endemic areas, as well as in vaccine trials. It will also be valuable for optimizing the MSP1(19) antigen by rational vaccine design. This work also shows that TROSY NMR techniques are very effective for mapping conformational epitopes at the level of individual residues on small- to medium-sized proteins, provided that the antigen can be expressed in a system amenable to stable isotope labelling, such as bacteria or yeast.
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PMID:Malaria parasite-inhibitory antibody epitopes on Plasmodium falciparum merozoite surface protein-1(19) mapped by TROSY NMR. 1550 Sep 13

We have applied NMR cross-saturation with TROSY detection to the problem of precisely mapping conformational epitopes on complete protein antigen molecules. We have investigated complexes of the Fab fragments of two antibodies that have parasite inhibitory activity, bound to the important malaria vaccine candidate antigen, Plasmodium falciparum MSP1(19). The results indicate remarkable overlap between these epitopes for inhibitory antibodies, and will provide a basis for theoretical modeling of the antibody-antigen interface.
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PMID:Precise epitope mapping of malaria parasite inhibitory antibodies by TROSY NMR cross-saturation. 1564 76

EBA-175 protein is used as ligand in Plasmodium falciparum binding to erythrocytes. Evidence shows that conserved peptide 1815 from this protein having high red blood cell binding ability plays an important role in the invasion process. This peptide is neither immunogenic nor protective. Residues were substituted by amino acids having similar volume or mass but different polarity in 1815 analogues had to make them fit into HLA-DRbeta1*03 molecules; these were synthesised and inoculated into Aotus monkeys, generating different immunogenic and/or protective immune responses. A shortening in alpha-helix structure was found in the immunogenic and protective ones when their secondary structure was analyzed by NMR to correlate their structure with their immunological properties. This data, together with results from previous studies, suggests that this shortening in high-activity binding peptide (HABP) helical configuration may lead to better fitting into immune system molecules as shown by binding to purified HLA-DRbeta1* molecules rendering them immunogenic and protective and therefore, excellent candidates for consideration as components of a subunit based multi-component synthetic vaccine against malaria.
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PMID:Evidence supporting the hypothesis that specifically modifying a malaria peptide to fit into HLA-DRbeta1*03 molecules induces antibody production and protection. 1569 10

The ethyl acetate extract from the Streptomyces sp. isolate B8652 delivered the trioxacarcins A to approximately C (2a to approximately 2c) and additionally three new derivatives designated as trioxacarcins D to approximately F (2d to approximately 2f). All trioxacarcins showed high anti-bacterial and some of them high anti-tumor and anti-malaria activity. The structures of the new antibiotics were derived from mass, 1D and 2D NMR spectra and confirmed by comparison of the NMR data with those of known derivatives. The absolute configuration of the trioxacarcins is deduced from the X-ray analysis of gutingimycin (2g) and from the known stereochemistry of the L-trioxacarcinoses A and B.
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PMID:Anti-cancer and antibacterial trioxacarcins with high anti-malaria activity from a marine Streptomycete and their absolute stereochemistry. 1574 11

The search for a rational method of developing an antimalarial vaccine (malaria caused by Plasmodium falciparum) consists of blocking receptor-ligand interaction. Conserved peptides derived from proteins involved in invasion and having strong red blood cell binding ability have thus been identified; immunization studies using Aotus monkeys revealed that these peptides were neither immunogenic nor protection-inducing. Some of these peptides induced long-lasting and very high antibody titers and protection when their critical red blood cell binding residues were replaced to change their immunological properties. Others induced short-lived antibodies that were not associated with inducing protection. The three-dimensional structure of the short-lived antibody-inducing peptide was determined by (1)H NMR. Their HLA-DRbeta1* molecule binding ability was also determined to ascertain the relationship among three-dimensional structure, their ability to bind to major histocompatibility complex class II molecules (MHC II), and possible short-lived antibody production. These short-lived antibody-inducing peptides were 6.8 +/- 0.5 A shorter between those residues theoretically coming into contact with pocket 1 and pocket 9 of HLA-DRbeta1* molecules to which they bind than immunogenic and protection-inducing peptides. These more compact alpha-helical structures suggest that these short-lived antibody-inducing peptides could have a structure more similar to those of native peptides than immunogenic and protective ones. Such shortening was associated with a shift in HLA-DRbeta1* molecule binding and a consequent shift in functional register reading, mainly by alleles of the same haplotype when compared with immunogenic protection-inducing HABPs, suggesting an imperfect and different conformation of the MHC II peptide-TCR complex.
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PMID:Peptides inducing short-lived antibody responses against Plasmodium falciparum malaria have shorter structures and are read in a different MHC II functional register. 1586 20

The malarial surface antigen apical membrane antigen (AMA1), from Plasmodium falciparum, is a leading candidate for inclusion in a vaccine against malaria. AMA1 is synthesised by mature blood-stages of the parasite and is located initially in the apical organelles of the merozoite. Prior to merozoite invasion of host erythrocytes, it is processed into a 66 kDa type 1 integral membrane protein on the merozoite surface. The pattern of disulphide bonds in AMA1 has been the basis for separation of the ectodomain into three domains, with three, two and three disulphide bonds, respectively. We have determined the solution structure of a 16kDa construct corresponding to the putative second domain of AMA1. While circular dichroism and hydrodynamic data were consistent with a folded structure for domain II, its NMR spectra were characterised by broad lines and significant peak overlap, more typical of a molten globule. Consistent with this, domain II bound the fluorescent dye 8-anilino-1-naphthalene sulphonate (ANS). We have nonetheless determined a structure, which defines the secondary structure elements and global fold. The two disulphide bonds link the N and C-terminal regions of the molecule, which come together to form a four-stranded beta-sheet linked to a short helix. A long loop linking the N and C-terminal regions contains four other alpha-helices, the locations of which are not fixed relative to the beta-sheet core, even though they are well-defined locally. Very recently this region of domain II has been shown to contain the epitope recognised by the invasion-inhibitory antibody 4G2, even though it does not contain any of the polymorphisms that are regarded as having arisen in response to the pressure of immune recognition.
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PMID:Structure and inter-domain interactions of domain II from the blood-stage malarial protein, apical membrane antigen 1. 1596 19

IPP (isopentenyl diphosphate) and DMAPP (dimethylallyl diphosphate) serve as the universal precursors for the biosynthesis of isoprenoids. Besides the well-known mevalonate pathway, the existence of a second biosynthetic pathway conducive to IPP and DMAPP formation through 1-deoxy-D-xylulose 5-phosphate and 2C-methyl-D-erythritol 4-phosphate was discovered approx. 10 years ago in plants and certain eubacteria. It is now known that this pathway is widely distributed in the bacterial kingdom including major human pathogens, such as Mycobacterium tuberculosis and Helicobacter pylori. The pathway is also essential in the malaria vector Plasmodium falciparum. During the last few years, the genes, enzymes, intermediates and mechanisms of the biosynthetic route have been elucidated by a combination of comparative genomics, enzymology, advanced NMR technology and crystallography. The results provide the basis for the development of novel anti-infective drugs.
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PMID:Isoprenoid biosynthetic pathways as anti-infective drug targets. 1604 99

Developing a logical and rational methodology for obtaining vaccines, especially against the main parasite causing human malaria (P. falciparum), consists of blocking receptor-ligand interactions. Conserved peptides derived from proteins involved in invasion and having high red blood cell binding ability have thus been identified. Immunization studies using Aotus monkeys have revealed that these peptides were neither immunogenic nor protection inducing. When modified in their critical binding residues, previously identified by Glycine scanning, some of these peptides were immunogenic and non-protection inducers; others induced short-lived antibodies whilst a few were both immunogenic and protection inducing. However, very few of these modified high activity binding peptides (HABPs) reproducibly induced protection without inducing antibody production, but with high cytokine liberation, suggesting that cellular mechanisms had been activated in the protection process. The three-dimensional structure of these peptides inducing protection without producing antibodies was determined by 1H-NMR. Their HLA-DRbeta1* molecule binding ability was also determined to ascertain association between their 3D structure and ability to bind to Major Histocompatibility Complex Class-II molecules (MHC-II). 1H Nuclear Magnetic Resonance analysis and structure calculations clearly showed that these modified HABPs inducing protective cellular immune responses (but not producing antibodies against malaria) adopted special structural configuration to fit into the MHC II-peptide-TCR complex. A different orientation for P7 and P8 TCR contacting residues was clearly recognized when comparing their structure with modified peptides, which induced high antibody titers and protection, suggesting that these residues are involved in activating the immune system associated with antibody production and protection.
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PMID:Protective cellular immunity against P. falciparum malaria merozoites is associated with a different P7 and P8 residue orientation in the MHC-peptide-TCR complex. 1612 20


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