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Synthesis and antimalarial activity of prodigiosenes.
Marchal E, Smithen DA, Uddin MI, Robertson AW, Jakeman DL, Mollard V, Goodman CD, MacDougall KS, McFarland SA, McFadden GI, Thompson A
(2014) Org Biomol Chem 12: 4132-42
MeSH Terms: Antimalarials, Coordination Complexes, Parasitic Sensitivity Tests, Plasmodium falciparum, Prodigiosin, Tin, Zinc
Show Abstract · Added December 29, 2016
Several analogues of the natural compound prodigiosin with modified A- and C-rings were synthesised as were some of their tin, cobalt, boron and zinc complexes. The antimalarial activity of these prodigiosenes was evaluated in vitro using the 3D7 Plasmodium falciparum strain. The presence of a nitrogen atom in the A-ring is needed for antimalarial activity but the presence of an alkyl group at the β'-position of the C-ring seems detrimental. Dibutyl tin complexes exhibit IC50 values mostly in the nanomolar range with equal or improved activity compared to the free-base prodigiosene ligand, despite the fact that the general toxicity of such tin complexes is demonstrably lower than that of the free-bases.
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7 MeSH Terms
Coffee rings as low-resource diagnostics: detection of the malaria biomarker Plasmodium falciparum histidine-rich protein-II using a surface-coupled ring of Ni(II)NTA gold-plated polystyrene particles.
Gulka CP, Swartz JD, Trantum JR, Davis KM, Peak CM, Denton AJ, Haselton FR, Wright DW
(2014) ACS Appl Mater Interfaces 6: 6257-63
MeSH Terms: Animals, Antigens, Protozoan, Biomarkers, Gold, Malaria, Falciparum, Microscopy, Electron, Transmission, Plasmodium falciparum, Polystyrenes, Protozoan Proteins, Surface Properties, Titanium
Show Abstract · Added May 27, 2014
We report a novel, low-resource malaria diagnostic platform inspired by the coffee ring phenomenon, selective for Plasmodium falciparum histidine-rich protein-II (PfHRP-II), a biomarker indicative of the P. falciparum parasite strain. In this diagnostic design, a recombinant HRP-II (rcHRP-II) biomarker is sandwiched between 1 μm Ni(II)nitrilotriacetic acid (NTA) gold-plated polystyrene microspheres (AuPS) and Ni(II)NTA-functionalized glass. After rcHRP-II malaria biomarkers had reacted with Ni(II)NTA-functionalized particles, a 1 μL volume of the particle-protein conjugate solution is deposited onto a functionalized glass slide. Drop evaporation produces the radial flow characteristic of coffee ring formation, and particle-protein conjugates are transported toward the drop edge, where, in the presence of rcHRP-II, particles bind to the Ni(II)NTA-functionalized glass surface. After evaporation, a wash with deionized water removes nonspecifically bound materials while maintaining the integrity of the surface-coupled ring produced by the presence of the protein biomarker. The dynamic range of this design was found to span 3 orders of magnitude, and rings are visible with the naked eye at protein concentrations as low as 10 pM, 1 order of magnitude below the 100 pM PfHRP-II threshold recommended by the World Health Organization. Key enabling features of this design are the inert and robust gold nanoshell to reduce nonspecific interactions on the particle surface, inclusion of a water wash step after drop evaporation to reduce nonspecific binding to the glass, a large diameter particle to project a large two-dimensional viewable area after ring formation, and a low particle density to favor radial flow toward the drop edge and reduce vertical settling to the glass surface in the center of the drop. This robust, antibody-free assay offers a simple user interface and clinically relevant limits of biomarker detection, two critical features required for low-resource malaria detection.
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11 MeSH Terms
Development of a histidine-targeted spectrophotometric sensor using Ni(II)NTA-functionalized Au and Ag nanoparticles.
Swartz JD, Gulka CP, Haselton FR, Wright DW
(2011) Langmuir 27: 15330-9
MeSH Terms: Amino Acid Sequence, Antigens, Protozoan, Colloids, Gold, Histidine, Humans, Hydrogen-Ion Concentration, Malaria, Falciparum, Metal Nanoparticles, Microscopy, Electron, Transmission, Molecular Mimicry, Molecular Sequence Data, Nickel, Nitrilotriacetic Acid, Peptides, Plasmodium falciparum, Protozoan Proteins, Reagent Kits, Diagnostic, Silver, Spectrophotometry
Show Abstract · Added May 27, 2014
An antibody-free diagnostic reagent has been developed based on the aggregation-induced colorimetric change of Ni(II)NTA-functionalized colloidal gold and silver nanoparticles. This diagnostic strategy utilizes the high binding affinity of histidine-rich proteins with Ni(II)NTA to capture and cross-link the histidine-rich protein mimics with the silver and gold nanoparticles. In model studies, the aggregation behavior of the Ni(II)NTA nanoparticles was tested against synthetic targets including charged poly(amino acid)s (histidine, lysine, arginine, and aspartic acid) and mimics of Plasmodium falciparum histidine-rich protein 2 (pfHRP-II). Aggregation of the nanoparticle sensor was induced by all of the basic poly(amino acid)s including poly(l-histidine) within the pH range (5.5-9.0) tested, which is likely caused by the coordination between the multivalent polymer target and Ni(II)NTA groups on multiple particles. The peptide mimics induced aggregation of the nanoparticles only near their pK(a)'s with higher limits of detection. In addition, monomeric amino acids do not show any aggregation behavior, suggesting that multiple target binding sites are necessary for aggregation. Long-term stability studies showed that gold but not silver nanoparticles remained stable and exhibited similar aggregation behavior after 1 month of storage at room temperature and 37 °C. These results suggest that Ni(II)NTA gold nanoparticles could be further investigated for use as a sensor to detect histidine-rich proteins in biological samples.
© 2011 American Chemical Society
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20 MeSH Terms
Cytoplasmic remodeling of erythrocyte raft lipids during infection by the human malaria parasite Plasmodium falciparum.
Murphy SC, Fernandez-Pol S, Chung PH, Prasanna Murthy SN, Milne SB, Salomao M, Brown HA, Lomasney JW, Mohandas N, Haldar K
(2007) Blood 110: 2132-9
MeSH Terms: Animals, Annexin A5, Blotting, Western, Cell Membrane, Cytoplasm, Endocytosis, Erythrocyte Membrane, Erythrocytes, Flow Cytometry, Green Fluorescent Proteins, Humans, Isoenzymes, Liposomes, Malaria, Mass Spectrometry, Membrane Microdomains, Parasitemia, Phosphatidylethanolamines, Phosphatidylglycerols, Phosphatidylinositol 4,5-Diphosphate, Phosphatidylinositols, Phospholipase C delta, Plasmodium falciparum, Primaquine, Type C Phospholipases, Vacuoles
Show Abstract · Added March 21, 2013
Studies of detergent-resistant membrane (DRM) rafts in mature erythrocytes have facilitated identification of proteins that regulate formation of endovacuolar structures such as the parasitophorous vacuolar membrane (PVM) induced by the malaria parasite Plasmodium falciparum. However, analyses of raft lipids have remained elusive because detergents interfere with lipid detection. Here, we use primaquine to perturb the erythrocyte membrane and induce detergent-free buoyant vesicles, which are enriched in cholesterol and major raft proteins flotillin and stomatin and contain low levels of cytoskeleton, all characteristics of raft microdomains. Lipid mass spectrometry revealed that phosphatidylethanolamine and phosphatidylglycerol are depleted in endovesicles while phosphoinositides are highly enriched, suggesting raft-based endovesiculation can be achieved by simple (non-receptor-mediated) mechanical perturbation of the erythrocyte plasma membrane and results in sorting of inner leaflet phospholipids. Live-cell imaging of lipid-specific protein probes showed that phosphatidylinositol (4,5) bisphosphate (PIP(2)) is highly concentrated in primaquine-induced vesicles, confirming that it is an erythrocyte raft lipid. However, the malarial PVM lacks PIP(2), although another raft lipid, phosphatidylserine, is readily detected. Thus, different remodeling/sorting of cytoplasmic raft phospholipids may occur in distinct endovacuoles. Importantly, erythrocyte raft lipids recruited to the invasion junction by mechanical stimulation may be remodeled by the malaria parasite to establish blood-stage infection.
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26 MeSH Terms
Enhanced immunity to Plasmodium falciparum circumsporozoite protein (PfCSP) by using Salmonella enterica serovar Typhi expressing PfCSP and a PfCSP-encoding DNA vaccine in a heterologous prime-boost strategy.
Chinchilla M, Pasetti MF, Medina-Moreno S, Wang JY, Gomez-Duarte OG, Stout R, Levine MM, Galen JE
(2007) Infect Immun 75: 3769-79
MeSH Terms: Amino Acid Sequence, Animals, Antibodies, Protozoan, Bacterial Proteins, Cells, Cultured, Epitopes, Female, Genetic Vectors, Hemolysin Proteins, Immunity, Mucosal, Immunization, Secondary, Interferon-gamma, Leukocytes, Mononuclear, Malaria Vaccines, Mice, Mice, Inbred BALB C, Models, Animal, Molecular Sequence Data, Plasmodium falciparum, Protozoan Proteins, Recombinant Fusion Proteins, Salmonella typhi, Vaccines, DNA
Show Abstract · Added May 27, 2014
Two Salmonella enterica serovar Typhi strains that express and export a truncated version of Plasmodium falciparum circumsporozoite surface protein (tCSP) fused to Salmonella serovar Typhi cytolysin A (ClyA) were constructed as a first step in the development of a preerythrocytic malaria vaccine. Synthetic codon-optimized genes (t-csp1 and t-csp2), containing immunodominant B- and T-cell epitopes present in native P. falciparum circumsporozoite surface protein (PfCSP), were fused in frame to the carboxyl terminus of the ClyA gene (clyA::t-csp) in genetically stabilized expression plasmids. Expression and export of ClyA-tCSP1 and ClyA-tCSP2 by Salmonella serovar Typhi vaccine strain CVD 908-htrA were demonstrated by immunoblotting of whole-cell lysates and culture supernatants. The immunogenicity of these constructs was evaluated using a "heterologous prime-boost" approach consisting of mucosal priming with Salmonella serovar Typhi expressing ClyA-tCSP1 and ClyA-tCSP2, followed by parenteral boosting with PfCSP DNA vaccines pVR2510 and pVR2571. Mice primed intranasally on days 0 and 28 with CVD 908-htrA(pSEC10tcsp2) and boosted intradermally on day 56 with PfCSP DNA vaccine pVR2571 induced high titers of serum NANP immunoglobulin G (IgG) (predominantly IgG2a); no serological responses to DNA vaccination were observed in the absence of Salmonella serovar Typhi-PfCSP priming. Mice primed with Salmonella serovar Typhi expressing tCSP2 and boosted with PfCSP DNA also developed high frequencies of gamma interferon-secreting cells, which surpassed those produced by PfCSP DNA in the absence of priming. A prime-boost regimen consisting of mucosal delivery of PfCSP exported from a Salmonella-based live-vector vaccine followed by a parenteral PfCSP DNA boosting is a promising strategy for the development of a live-vector-based malaria vaccine.
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23 MeSH Terms
Structure of the regulatory apparatus of a calcium-dependent protein kinase (CDPK): a novel mode of calmodulin-target recognition.
Chandran V, Stollar EJ, Lindorff-Larsen K, Harper JF, Chazin WJ, Dobson CM, Luisi BF, Christodoulou J
(2006) J Mol Biol 357: 400-10
MeSH Terms: Amino Acid Sequence, Animals, Arabidopsis, Calcium, Calcium-Binding Proteins, Calmodulin, Crystallography, X-Ray, Dimerization, Isoenzymes, Models, Molecular, Molecular Sequence Data, Peptides, Plant Proteins, Plasmodium falciparum, Protein Conformation, Protein Kinases, Sequence Alignment
Show Abstract · Added December 10, 2013
Calcium-dependent protein kinases (CDPKs) are a class of calcium-binding sensory proteins that are found in plants and certain protozoa, including the causative agent of malaria, Plasmodium falciparum. CDPKs have diverse regulatory functions, including involvement in the triggering of the lytic cycle of malarial infection. CDPKs contain an autoinhibitory junction (J) region whose calcium-dependent interaction with the tethered regulatory calmodulin-like domain (CaM-LD) activates the catalytic kinase domain. We report here the X-ray crystal structure of the J-CaM-LD region of CDPK from Arabidopsis thaliana (AtCPK1), determined to 2.0 A resolution using multiple-wavelength anomalous dispersion (MAD). The structure reveals a symmetric dimer of calcium-bound J-CaM-LD with domain-swap interactions, in which the J region of one protomer interacts extensively with the carboxy-terminal EF-hand domain (C-lobe) of the partner protomer. However, as the J-CaM-LD is monomeric in solution, the activated monomer was modelled to account for the intra-molecular recognition of the two domains. While the J-CaM-LD segment mimics certain aspects of target motif recognition by CaM other features are specific to CDPKs, in particular the combination of the strong interaction between the N and C-lobes of the CaM-LD and the exclusive use of only the C-lobe in the recognition of the covalently tethered target region. Combined with our previous observations showing that there is likely to be strong interactions between this tethered J region and the CaM-LD even at basal Ca(2+) concentrations, the new structural data indicate that the response to calcium of CDPKs is clearly unique among the CaM family.
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17 MeSH Terms
O-sulfonation of serine and threonine: mass spectrometric detection and characterization of a new posttranslational modification in diverse proteins throughout the eukaryotes.
Medzihradszky KF, Darula Z, Perlson E, Fainzilber M, Chalkley RJ, Ball H, Greenbaum D, Bogyo M, Tyson DR, Bradshaw RA, Burlingame AL
(2004) Mol Cell Proteomics 3: 429-40
MeSH Terms: Animals, Chromatography, Liquid, Cloning, Molecular, Humans, Lymnaea, Mass Spectrometry, Myosin Light Chains, Peptides, Plasmodium falciparum, Protein Processing, Post-Translational, Protozoan Proteins, Receptor Tyrosine Kinase-like Orphan Receptors, Receptors, Cell Surface, Serine, Threonine
Show Abstract · Added February 27, 2013
Protein sulfonation on serine and threonine residues is described for the first time. This post-translational modification is shown to occur in proteins isolated from organisms representing a broad span of eukaryote evolution, including the invertebrate mollusk Lymnaea stagnalis, the unicellular malaria parasite Plasmodium falciparum, and humans. Detection and structural characterization of this novel post-translational modification was carried out using liquid chromatography coupled to electrospray tandem mass spectrometry on proteins including a neuronal intermediate filament and a myosin light chain from the snail, a cathepsin-C-like enzyme from the parasite, and the cytoplasmic domain of the human orphan receptor tyrosine kinase Ror-2. These findings suggest that sulfonation of serine and threonine may be involved in multiple functions including protein assembly and signal transduction.
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15 MeSH Terms
Erythrocyte G protein-coupled receptor signaling in malarial infection.
Harrison T, Samuel BU, Akompong T, Hamm H, Mohandas N, Lomasney JW, Haldar K
(2003) Science 301: 1734-6
MeSH Terms: Adrenergic beta-2 Receptor Agonists, Adrenergic beta-2 Receptor Antagonists, Adrenergic beta-Agonists, Adrenergic beta-Antagonists, Alprenolol, Animals, Catecholamines, Cyclic AMP, Erythrocyte Membrane, Erythrocytes, GTP-Binding Protein alpha Subunits, Gs, Humans, Malaria, Membrane Microdomains, Mice, Parasitemia, Peptide Fragments, Plasmodium berghei, Plasmodium falciparum, Propranolol, Purinergic P1 Receptor Agonists, Purinergic P1 Receptor Antagonists, Receptors, Adrenergic, beta-2, Receptors, Purinergic P1, Signal Transduction, Stereoisomerism, Vacuoles
Show Abstract · Added December 10, 2013
Erythrocytic mechanisms involved in malarial infection are poorly understood. We have found that signaling via the erythrocyte beta2-adrenergic receptor and heterotrimeric guanine nucleotide-binding protein (Galphas) regulated the entry of the human malaria parasite Plasmodium falciparum. Agonists that stimulate cyclic adenosine 3',5'-monophosphate production led to an increase in malarial infection that could be blocked by specific receptor antagonists. Moreover, peptides designed to inhibit Galphas protein function reduced parasitemia in P. falciparum cultures in vitro, and beta-antagonists reduced parasitemia of P. berghei infections in an in vivo mouse model. Thus, signaling via the erythrocyte beta2-adrenergic receptor and Galphas may regulate malarial infection across parasite species.
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27 MeSH Terms
A proteomic view of the Plasmodium falciparum life cycle.
Florens L, Washburn MP, Raine JD, Anthony RM, Grainger M, Haynes JD, Moch JK, Muster N, Sacci JB, Tabb DL, Witney AA, Wolters D, Wu Y, Gardner MJ, Holder AA, Sinden RE, Yates JR, Carucci DJ
(2002) Nature 419: 520-6
MeSH Terms: Animals, Antimalarials, Chromosomes, Erythrocytes, Female, Genome, Protozoan, Germ Cells, Humans, Life Cycle Stages, Malaria Vaccines, Male, Plasmodium falciparum, Proteome, Protozoan Proteins
Show Abstract · Added March 5, 2014
The completion of the Plasmodium falciparum clone 3D7 genome provides a basis on which to conduct comparative proteomics studies of this human pathogen. Here, we applied a high-throughput proteomics approach to identify new potential drug and vaccine targets and to better understand the biology of this complex protozoan parasite. We characterized four stages of the parasite life cycle (sporozoites, merozoites, trophozoites and gametocytes) by multidimensional protein identification technology. Functional profiling of over 2,400 proteins agreed with the physiology of each stage. Unexpectedly, the antigenically variant proteins of var and rif genes, defined as molecules on the surface of infected erythrocytes, were also largely expressed in sporozoites. The detection of chromosomal clusters encoding co-expressed proteins suggested a potential mechanism for controlling gene expression.
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14 MeSH Terms
Expression, extracellular secretion, and immunogenicity of the Plasmodium falciparum sporozoite surface protein 2 in Salmonella vaccine strains.
Gómez-Duarte OG, Pasetti MF, Santiago A, Sztein MB, Hoffman SL, Levine MM
(2001) Infect Immun 69: 1192-8
MeSH Terms: Animals, Antigens, Protozoan, Female, Immunization, Lymphocyte Activation, Malaria Vaccines, Mice, Mice, Inbred C57BL, Molecular Weight, Plasmodium falciparum, Protozoan Proteins, Salmonella, T-Lymphocytes, Cytotoxic, Vaccines, DNA
Show Abstract · Added May 27, 2014
Deleting transmembrane alpha-helix motifs from Plasmodium falciparum sporozoite surface protein (SSP-2) allowed its secretion from Salmonella enterica serovar Typhimurium SL3261 and S. enterica serovar Typhi CVD 908-htrA by the Hly type I secretion system. In mice immunized intranasally, serovar Typhimurium constructs secreting SSP-2 stimulated greater gamma interferon splenocyte responses than did nonsecreting constructs (P = 0.04).
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14 MeSH Terms