Journal articles: 'Plasmodial Proteins'

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Musyoka, Thommas, and Özlem Tastan Bishop. "South African Abietane Diterpenoids and Their Analogs as Potential Antimalarials: Novel Insights from Hybrid Computational Approaches." Molecules 24, no. 22 (November 7, 2019): 4036. http://dx.doi.org/10.3390/molecules24224036.

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The hemoglobin degradation process in Plasmodium parasites is vital for nutrient acquisition required for their growth and proliferation. In P. falciparum, falcipains (FP-2 and FP-3) are the major hemoglobinases, and remain attractive antimalarial drug targets. Other Plasmodium species also possess highly homologous proteins to FP-2 and FP-3. Although several inhibitors have been designed against these proteins, none has been commercialized due to associated toxicity on human cathepsins (Cat-K, Cat-L and Cat-S). Despite the two enzyme groups sharing a common structural fold and catalytic mechanism, distinct active site variations have been identified, and can be exploited for drug development. Here, we utilize in silico approaches to screen 628 compounds from the South African natural sources to identify potential hits that can selectively inhibit the plasmodial proteases. Using docking studies, seven abietane diterpenoids, binding strongly to the plasmodial proteases, and three additional analogs from PubChem were identified. Important residues involved in ligand stabilization were identified for all potential hits through binding pose analysis and their energetic contribution determined by binding free energy calculations. The identified compounds present important scaffolds that could be further developed as plasmodial protease inhibitors. Previous laboratory assays showed the effect of the seven diterpenoids as antimalarials. Here, for the first time, we demonstrate that their possible mechanism of action could be by interacting with falcipains and their plasmodial homologs. Dynamic residue network (DRN) analysis on the plasmodial proteases identified functionally important residues, including a region with high betweenness centrality, which had previously been proposed as a potential allosteric site in FP-2.

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Gayathri, P., Hemalatha Balaram, and MRN Murthy. "Structural biology of plasmodial proteins." Current Opinion in Structural Biology 17, no. 6 (December 2007): 744–54. http://dx.doi.org/10.1016/j.sbi.2007.08.001.

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Shonhai, Addmore. "Plasmodial heat shock proteins: targets for chemotherapy." FEMS Immunology & Medical Microbiology 58, no. 1 (February 2010): 61–74. http://dx.doi.org/10.1111/j.1574-695x.2009.00639.x.

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Adisa, Akinola, Frank R. Albano, John Reeder, Michael Foley, and Leann Tilley. "Evidence for a role for a Plasmodium falciparum homologue of Sec31p in the export of proteins to the surface of malaria parasite-infected erythrocytes." Journal of Cell Science 114, no. 18 (September 15, 2001): 3377–86. http://dx.doi.org/10.1242/jcs.114.18.3377.

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The malaria parasite, Plasmodium falciparum, spends part of its life cycle inside the enucleated erythrocytes of its human host. The parasite modifies the cytoplasm and plasma membrane of its host cell by exporting proteins beyond the confines of its own plasma membrane. We have previously provided evidence that a plasmodial homologue of the COPII protein, Sar1p, is involved in the trafficking of proteins across the erythrocyte cytoplasm. We have now characterised an additional plasmodial COPII protein homologue, namely Sec31p. Recombinant proteins corresponding to the WD-40 and the intervening domains of the PfSec31p sequence were used to raise antibodies. The affinity-purified antisera recognised a protein with an apparent relative molecular mass of 1.6×105 on western blots of malaria parasite-infected erythrocytes but not on blots of uninfected erythrocytes. PfSec31p was shown to be largely insoluble in nonionic detergent, suggesting cytoskeletal attachment. Confocal immunofluorescence microscopy of malaria parasite-infected erythrocytes was used to show that PfSec31p is partly located within the parasite and partly exported to structures outside the parasite in the erythrocyte cytoplasm. We have also shown that PfSec31p and PfSar1p occupy overlapping locations. Furthermore, the location of PfSec31p overlaps that of the cytoadherence-mediating protein PfEMP1. These data support the suggestion that the malaria parasite establishes a vesicle-mediated trafficking pathway outside the boundaries of its own plasma membrane – a novel paradigm in eukaryotic biology.

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Pizzi, Elisabetta, and Clara Frontali. "Low-Complexity Regions in Plasmodium falciparum Proteins." Genome Research 11, no. 2 (January 18, 2001): 218–29. http://dx.doi.org/10.1101/gr.152201.

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Full-sequence data available for Plasmodium falciparumchromosomes 2 and 3 are exploited to perform a statistical analysis of the long tracts of biased amino acid composition that characterize the vast majority of P. falciparum proteins and to make a comparison with similarly defined tracts from other simple eukaryotes. When the relatively minor subset of prevalently hydrophobic segments is discarded from the set of low-complexity segments identified by current segmentation methods in P. falciparum proteins, a good correspondence is found between prevalently hydrophilic low-complexity segments and the species-specific, rapidly diverging insertions detected by multiple-alignment procedures when sequences of bona fide homologs are available. Amino acid preferences are fairly uniform in the set of hydrophilic low-complexity segments identified in the twoP. falciparum chromosomes sequenced, as well as in sequenced genes from Plasmodium berghei, but differ from those observed in Saccharomyces cerevisiae and Dictyostelium discoideum. In the two plasmodial species, amino acid frequencies do not correlate with properties such as hydrophilicity, small volume, or flexibility, which might be expected to characterize residues involved in nonglobular domains but do correlate with A-richness in codons. An effect of phenotypic selection versus neutral drift, however, is suggested by the predominance of asparagine over lysine.

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Wunderlich, Gerhard, Fabiana P. Alves, Uta Gölnitz, Mauro S. Tada, Erney F. P. de Camargo, and Luiz H. Pereira-da-Silva. "Rapid turnover of Plasmodium falciparum var gene transcripts and genotypes during natural non-symptomatic infections." Revista do Instituto de Medicina Tropical de São Paulo 47, no. 4 (August 2005): 195–201. http://dx.doi.org/10.1590/s0036-46652005000400004.

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The var genes of Plasmodium falciparum code for the antigenically variant erythrocyte membrane proteins 1 (PfEMP1), a major factor for cytoadherence and immune escape of the parasite. Herein, we analyzed the var gene transcript turnover in two ongoing, non-symptomatic infections at sequential time points during two weeks. The number of different circulating genomes was estimated by microsatellite analyses. In both infections, we observed a rapid turnover of plasmodial genotypes and var transcripts. The rapidly changing repertoire of var transcripts could have been caused either by swift elimination of circulating var-transcribing parasites stemming from different or identical genetic backgrounds, or by accelerated switching of var gene transcription itself.

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Birkholtz, Lyn-Marie, Gregory Blatch, Theresa L. Coetzer, Heinrich C. Hoppe, Esmaré Human, Elizabeth J. Morris, Zoleka Ngcete, et al. "Heterologous expression of plasmodial proteins for structural studies and functional annotation." Malaria Journal 7, no. 1 (2008): 197. http://dx.doi.org/10.1186/1475-2875-7-197.

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PESCE, E. R., and G. L. BLATCH. "Plasmodial Hsp40 and Hsp70 chaperones: current and future perspectives." Parasitology 141, no. 9 (March 25, 2014): 1167–76. http://dx.doi.org/10.1017/s003118201300228x.

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SUMMARYPlasmodium falciparumdisplays a large and remarkable variety of heat shock protein 40 family members (PfHsp40s). The majority of the PfHsp40s are poorly characterized, and although the functions of some of them have been suggested, their exact mechanism of action is still elusive and their interacting partners and client proteins are unknown. TheP. falciparumheat shock protein 70 family members (PfHsp70s) have been more extensively characterized than the PfHsp40s, with certain members shown to function as molecular chaperones. However, little is known about the PfHsp70-PfHsp40 chaperone partnerships. There is mounting evidence that these chaperones are important not only in protein homoeostasis and cytoprotection, but also in protein trafficking across the parasitophorous vacuole (PV) and into the infected erythrocyte. We propose that certain members of these chaperone families work together to maintain exported proteins in an unfolded state until they reach their final destination. In this review, we critically evaluate what is known and not known about PfHsp40s and PfHsp70s.

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Lindner, Jasmin, Kamila Anna Meissner, Isolmar Schettert, and Carsten Wrenger. "Trafficked Proteins—Druggable inPlasmodium falciparum?" International Journal of Cell Biology 2013 (2013): 1–13. http://dx.doi.org/10.1155/2013/435981.

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Malaria is an infectious disease that results in serious health problems in the countries in which it is endemic. Annually this parasitic disease leads to more than half a million deaths; most of these are children in Africa. An effective vaccine is not available, and the treatment of the disease is solely dependent on chemotherapy. However, drug resistance is spreading, and the identification of new drug targets as well as the development of new antimalarials is urgently required. Attention has been drawn to a variety of essential plasmodial proteins, which are targeted to intra- or extracellular destinations, such as the digestive vacuole, the apicoplast, or into the host cell. Interfering with the action or the transport of these proteins will impede proliferation of the parasite. In this mini review, we will shed light on the present discovery of chemotherapeutics and potential drug targets involved in protein trafficking processes in the malaria parasite.

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Chen, Xinlu, Tobias G. Köllner, Wangdan Xiong, Guo Wei, and Feng Chen. "Emission and biosynthesis of volatile terpenoids from the plasmodial slime mold Physarum polycephalum." Beilstein Journal of Organic Chemistry 15 (November 28, 2019): 2872–80. http://dx.doi.org/10.3762/bjoc.15.281.

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Terpene synthases (TPSs) are pivotal enzymes for the production of diverse terpenes, including monoterpenes, sesquiterpenes, and diterpenes. In our recent studies, dictyostelid social amoebae, also known as cellular slime molds, were found to contain TPS genes for making volatile terpenes. For comparison, here we investigated Physarum polycephalum, a plasmodial slime mold also known as acellular amoeba. Plasmodia of P. polycephalum grown on agar plates were found to release a mixture of volatile terpenoids consisting of four major sesquiterpenes (α-muurolene, (E)-β-caryophyllene, two unidentified sesquiterpenoids) and the monoterpene linalool. There were no qualitative differences in terpenoid composition at two stages of young plasmodia. To understand terpene biosynthesis, we analyzed the transcriptome and genome sequences of P. polycephalum and identified four TPS genes designated PpolyTPS1–PpolyTPS4. They share 28–73% of sequence identities. Full-length cDNAs for the four TPS genes were cloned and expressed in Escherichia coli to produce recombinant proteins, which were tested for sesquiterpene synthase and monoterpene synthase activities. While neither PpolyTPS2 nor PpolyTPS3 was active, PpolyTPS1 and PpolyTPS4 were able to produce sesquiterpenes and monoterpenes from the respective substrates farnesyl diphosphate and geranyl diphosphate. By comparing the volatile profile of P. polycephalum plasmodia and the in vitro products of PpolyTPS1 and PpolyTPS4, it was concluded that most sesquiterpenoids emitted from P. polycephalum were attributed to PpolyTPS4. Phylogenetic analysis placed the four PpolyTPSs genes into two groups: PpolyTPS1 and PpolyTPS4 being one group that was clustered with the TPSs from the dictyostelid social amoeba and PpolyTPS2 and PpolyTPS3 being the other group that showed closer relatedness to bacterial TPSs. The biological role of the volatile terpenoids produced by the plasmodia of P. polycephalum is discussed.

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Nwonuma, Charles Obiora, Elizabeth Abiodun Balogun, and Gideon Ampoma Gyebi. "Evaluation of Antimalarial Activity of Ethanolic Extract of Annona muricata L.: An in vivo and an in silico Approach." Journal of Evidence-Based Integrative Medicine 28 (January 2023): 2515690X2311651. http://dx.doi.org/10.1177/2515690x231165104.

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In Nigeria, Annona muricata L. has been used to treat a variety of ailments. The mechanism of the antimalarial activity of ethanolic leaf extract of Annona muricata (EEAML) was investigated using both an in vivo and an in silico approach. The experimental mice were divided into five groups: A-F. The mice in groups B-F were inoculated with Plasmodium berghei NK-65 and treated accordingly. Groups A and B are the negative and positive controls (infected and untreated), respectively. Group C received 10 mg/kg chloroquine (standard drug), whereas groups D-F received 100, 200, and 300 mg/kg body weight of the extract orally respectively. The mice were euthanized eight days after infection, and their liver and blood were collected and used in biochemical tests. Molecular docking was performed using the extract's HPLC compounds and Plasmodium falciparum proteins. In the suppressive, prophylactic, and curative tests, there was a significant decrease (p < 0.05) in parasitemia levels in groups treated with the extract compared to the positive control and standard drug. When compared to the positive control, there was a significant (p < 0.05) reduction in liver MDA, total cholesterol, and total triglyceride levels. The binding energies of luteolin and apigenin- pfprotein complexes were significantly (p < 0.05) higher compared to their respective references. The anti-plasmodial activity of the extract may result from its hypolipidemic effect, which deprives the parasite of essential lipid molecules needed for parasite growth, as well as from the inhibitory effects of apigenin and luteolin on specific proteins required for the Plasmodium metabolic pathway.

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Diggins, M. A., and W. F. Dove. "Distribution of acetylated alpha-tubulin in Physarum polycephalum." Journal of Cell Biology 104, no. 2 (February 1, 1987): 303–9. http://dx.doi.org/10.1083/jcb.104.2.303.

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The expression and cytological distribution of acetylated alpha-tubulin was investigated in Physarum polycephalum. A monoclonal antibody specific for acetylated alpha-tubulin, 6-11B-1 (Piperno, G., and M. T. Fuller, 1985, J. Cell Biol., 101:2085-2094), was used to screen for this protein during three different stages of the Physarum life cycle--the amoeba, the flagellate, and the plasmodium. Western blots of two-dimensional gels of amoebal and flagellate proteins reveal that this antibody recognizes the alpha 3 tubulin isotype, which was previously shown to be formed by posttranslational modification (Green, L. L., and W. F. Dove, 1984, Mol. Cell. Biol., 4:1706-1711). Double-label immunofluorescence demonstrates that, in the flagellate, acetylated alpha-tubulin is localized in the flagella and flagellar cone. Similar experiments with amoebae interestingly reveal that only within the microtubule organizing center (MTOC) are there detectable amounts of acetylated alpha-tubulin. In contrast, the plasmodial stage gives no evidence for acetylated alpha-tubulin by Western blotting or by immunofluorescence.

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Duval, Romain, Kevin Cottet, Magali Blaud, Anaïs Merckx, Sandrine Houzé, Philippe Grellier, Marie-Christine Lallemand, and Sylvie Michel. "A Photoalkylative Fluorogenic Probe of Guttiferone A for Live Cell Imaging and Proteome Labeling in Plasmodium falciparum." Molecules 25, no. 21 (November 4, 2020): 5139. http://dx.doi.org/10.3390/molecules25215139.

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Guttiferone A (GA) 1, a polycyclic polyprenylated acylphloroglucinol (PPAP) isolated from the plant Symphonia globulifera (Clusiaceae), constitutes a novel hit in antimalarial drug discovery. PPAPs do not possess identified biochemical targets in malarial parasites up to now. Towards this aim, we designed and evaluated a natural product-derived photoactivatable probe AZC-GA 5, embedding a photoalkylative fluorogenic motif of the 7-azidocoumarin (AZC) type, devoted to studying the affinity proteins interacting with GA in Plasmodium falciparum. Probe 5 manifested a number of positive functional and biological features, such as (i) inhibitory activity in vitro against P. falciparum blood-stages that was superimposable to that of GA 1, dose–response photoalkylative fluorogenic properties (ii) in model conditions using bovine serum albumin (BSA) as an affinity protein surrogate, (iii) in live P. falciparum-infected erythrocytes, and (iv) in fresh P. falciparum cell lysate. Fluorogenic signals by photoactivated AZC-GA 5 in biological settings were markedly abolished in the presence of excess GA 1 as a competitor, indicating significant pharmacological specificity of the designed molecular probe relative to the native PPAP. These results open the way to identify the detected plasmodial proteins as putative drug targets for the natural product 1 by means of proteomic analysis.

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Gupta, Ankit, Praveen Balabaskaran-Nina, Wang Nguitragool, Gagandeep S. Saggu, Marc A. Schureck, and Sanjay A. Desai. "CLAG3 Self-Associates in Malaria Parasites and Quantitatively Determines Nutrient Uptake Channels at the Host Membrane." mBio 9, no. 3 (May 8, 2018): e02293-17. http://dx.doi.org/10.1128/mbio.02293-17.

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ABSTRACT Malaria parasites increase host erythrocyte permeability to ions and nutrients via a broad-selectivity channel known as the plasmodial surface anion channel (PSAC), linked to parasite-encoded CLAG3 and two associated proteins. These proteins lack the multiple transmembrane domains typically present in channel-forming proteins, raising doubts about their precise roles. Using the virulent human Plasmodium falciparum parasite, we report that CLAG3 undergoes self-association and that this protein’s expression determines channel phenotype quantitatively. We overcame epigenetic silencing of clag3 paralogs and engineered parasites that express two CLAG3 isoforms simultaneously. Stoichiometric expression of these isoforms yielded intermediate channel phenotypes, in agreement with observed trafficking of both proteins to the host membrane. Coimmunoprecipitation and surface labeling revealed formation of CLAG3 oligomers. In vitro selections applied to these transfectant lines yielded distinct mutants with correlated changes in channel activity. These findings support involvement of the identified oligomers in PSAC formation and parasite nutrient acquisition. IMPORTANCE Malaria parasites are globally important pathogens that evade host immunity by replicating within circulating erythrocytes. To facilitate intracellular growth, these parasites increase erythrocyte nutrient uptake through an unusual ion channel. The parasite CLAG3 protein is a key determinant of this channel, but its lack of homology to known ion channels has raised questions about possible mechanisms. Using a new method that allows simultaneous expression of two different CLAG3 proteins, we identify self-association of CLAG3. The two expressed isoforms faithfully traffic to and insert in the host membrane, while remaining associated with two unrelated parasite proteins. Both the channel phenotypes and molecular changes produced upon selections with a highly specific channel inhibitor are consistent with a multiprotein complex that forms the nutrient pore. These studies support direct involvement of the CLAG3 protein in channel formation and are relevant to antimalarial drug discovery projects targeting parasite nutrient acquisition.

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Li, Wen-lu, Arpita Das, Ju-ying Song, Jay L. Crary, and Kasturi Haldar. "Stage-specific expression of plasmodial proteins containing an antigenic marker of the intraerythrocytic cisternae." Molecular and Biochemical Parasitology 49, no. 1 (November 1991): 157–68. http://dx.doi.org/10.1016/0166-6851(91)90138-v.

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Burns, James M., Carla C. Belk, and Patricia D. Dunn. "A Protective Glycosylphosphatidylinositol-Anchored Membrane Protein of Plasmodium yoelii Trophozoites and Merozoites Contains Two Epidermal Growth Factor-Like Domains." Infection and Immunity 68, no. 11 (November 1, 2000): 6189–95. http://dx.doi.org/10.1128/iai.68.11.6189-6195.2000.

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ABSTRACT Using sera from mice immunized and protected againstPlasmodium yoelii malaria, we identified a novel blood-stage antigen gene, pypag-2. The 2.1-kbpypag-2 cDNA contains a single open reading frame that encodes a 409-amino-acid protein with a predicted molecular mass of 46.8 kDa. Unlike many characterized plasmodial antigens, blocks of tandemly repeated amino acids are lacking in the pypAg-2 protein sequence. Recombinant pypAg-2, comprising the full-length protein minus the predicted N-terminal signal and C-terminal anchor sequences, was produced and used to raise a high-titer polyclonal rabbit antiserum. This antiserum was used to identify and characterize the native protein through immunoblotting, immunoprecipitation and immunofluorescence assays. Consistent with the presence of a glycosylphosphatidylinositol anchor, pypAg-2 fractionated with the detergent phase of Triton X-114-solubilized proteins and could be metabolically labeled with [3H]palmitic acid. By immunofluorescence, pypAg-2 expression was localized to both the trophozoite and merozoite membranes. Similar to Plasmodium falciparum merozoite surface protein 1, pypAg-2 contains two C-terminal epidermal growth factor (EGF)-like domains. Most importantly, immunization with recombinant pypAg-2 protected mice against lethal P. yoeliimalaria. Thus, pypAg-2 is a target of protective immune responses and represents a novel addition to the family of merozoite surface proteins that contain one or more EGF-like domains.

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Frugier, Magali, Tania Bour, Maya Ayach, Manuel A. S. Santos, Joëlle Rudinger-Thirion, Anne Théobald-Dietrich, and Elizabetta Pizzi. "Low Complexity Regions behave as tRNA sponges to help co-translational folding of plasmodial proteins." FEBS Letters 584, no. 2 (November 6, 2009): 448–54. http://dx.doi.org/10.1016/j.febslet.2009.11.004.

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Alkhalil, Abdulnaser, Jamieson V. Cohn, Marissa A. Wagner, Jennifer S. Cabrera, Thavamani Rajapandi, and Sanjay A. Desai. "Plasmodium falciparum likely encodes the principal anion channel on infected human erythrocytes." Blood 104, no. 13 (December 15, 2004): 4279–86. http://dx.doi.org/10.1182/blood-2004-05-2047.

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Abstract Invasion by the human malaria parasite, Plasmodium falciparum, is associated with marked yet selective increases in red blood cell (RBC) membrane permeability. We previously identified an unusual voltage-dependent ion channel, the plasmodial surface anion channel (PSAC), which may account for these increases. Since then, controversy has arisen about whether there are additional parasite-induced anion channels on the RBC membrane and whether these channels are parasite-encoded proteins or the result of modifications of an endogenous host protein. Here, we used genetically divergent parasite isolates and quantitative transport measurements to examine these questions. Our studies indicate that PSAC alone can adequately account for the increased permeability of infected RBCs to key solutes. Two distinct parasite isolates, grown in RBCs from a single donor, exhibit channel activity with measurably different voltage-dependent gating, a finding difficult to reconcile with simple activation or modification of a host protein. Instead, this difference in channel gating can be conservatively explained by a small number of polymorphisms in a parasite gene that encodes PSAC. The absence of known eukaryotic ion channel homologues in the completed P falciparum genome suggests a novel channel gene, and substantiates PSAC as a target for antimalarial development.

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Plebanski, M., M. Aidoo, H. C. Whittle, and A. V. Hill. "Precursor frequency analysis of cytotoxic T lymphocytes to pre-erythrocytic antigens of Plasmodium falciparum in West Africa." Journal of Immunology 158, no. 6 (March 15, 1997): 2849–55. http://dx.doi.org/10.4049/jimmunol.158.6.2849.

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Abstract Some individuals living in malaria-endemic areas have CTL to Plasmodium falciparum liver stage Ags. We have quantified these CTL responses using limiting dilution analysis studies on the peripheral blood cells of naturally exposed Gambian donors. CTL precursor frequencies were determined to a wide range of epitopes derived from different liver stage Ags (liver stage protein 1, circumsporozoite protein, thrombospondin-related anonymous protein, and sporozoite threonine/asparagine-rich protein) restricted through common HLA alleles present in this population (HLA-A2.1, -A2.2, -B7, -B8, -B35, and B53). Precursor frequencies were between 17 and 98/million PBMC and correlated with the levels of specific lysis in parallel bulk cultures. The quantitative nature of limiting dilution assay analysis revealed varying degrees of immunodominance in the CTL responses to different epitopes within single proteins (thrombospondin related anonymous protein: tr42, tr43, tr26, tr29, and tr39; circumsporozoite protein: cp6, cp26, and cp29) and within individual donors. The temporal stability of some of these CTL responses was determined over a 4-yr period. This is the first quantitative study of CTL specific for any plasmodial species or nonviral pathogen in humans and provides a basis for a multiepitope approach to malaria vaccination.

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Widada, Jaka, Ema Damayanti, Mustofa Mustofa, Achmad Dinoto, Rifki Febriansah, and Triana Hertiani. "Marine-Derived Streptomyces sennicomposti GMY01 with Anti-Plasmodial and Anticancer Activities: Genome Analysis, In Vitro Bioassay, Metabolite Profiling, and Molecular Docking." Microorganisms 11, no. 8 (July 28, 2023): 1930. http://dx.doi.org/10.3390/microorganisms11081930.

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To discover novel antimalarial and anticancer compounds, we carried out a genome analysis, bioassay, metabolite profiling, and molecular docking of marine sediment actinobacteria strain GMY01. The whole-genome sequence analysis revealed that Streptomyces sp. GMY01 (7.9 Mbp) is most similar to Streptomyces sennicomposti strain RCPT1-4T with an average nucleotide identity (ANI) and ANI based on BLAST+ (ANIb) values of 98.09 and 97.33% (>95%). An in vitro bioassay of the GMY01 bioactive on Plasmodium falciparum FCR3, cervical carcinoma of HeLa cell and lung carcinoma of HTB cells exhibited moderate activity (IC50 value of 46.06; 27.31 and 33.75 µg/mL) with low toxicity on Vero cells as a normal cell (IC50 value of 823.3 µg/mL). Metabolite profiling by LC-MS/MS analysis revealed that the active fraction of GMY01 contained carbohydrate-based compounds, C17H29NO14 (471.15880 Da) as a major compound (97.50%) and mannotriose (C18H32O16; 504.16903 Da, 1.96%) as a minor compound. Molecular docking analysis showed that mannotriose has a binding affinity on glutathione reductase (GR) and glutathione-S-transferase (GST) of P. falciparum and on autophagy proteins (mTORC1 and mTORC2) of cancer cells. Streptomyces sennicomposti GMY01 is a potential bacterium producing carbohydrate-based bioactive compounds with anti-plasmodial and anticancer activities and with low toxicity to normal cells.

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Lebepe, Charity Mekgwa, Pearl Rutendo Matambanadzo, Xolani Henry Makhoba, Ikechukwu Achilonu, Tawanda Zininga, and Addmore Shonhai. "Comparative Characterization of Plasmodium falciparum Hsp70-1 Relative to E. coli DnaK Reveals the Functional Specificity of the Parasite Chaperone." Biomolecules 10, no. 6 (June 4, 2020): 856. http://dx.doi.org/10.3390/biom10060856.

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Hsp70 is a conserved molecular chaperone. How Hsp70 exhibits specialized functions across species remains to be understood. Plasmodium falciparum Hsp70-1 (PfHsp70-1) and Escherichia coli DnaK are cytosol localized molecular chaperones that are important for the survival of these two organisms. In the current study, we investigated comparative structure-function features of PfHsp70-1 relative to DnaK and a chimeric protein, KPf, constituted by the ATPase domain of DnaK and the substrate binding domain (SBD) of PfHsp70-1. Recombinant forms of the three Hsp70s exhibited similar secondary and tertiary structural folds. However, compared to DnaK, both KPf and PfHsp70-1 were more stable to heat stress and exhibited higher basal ATPase activity. In addition, PfHsp70-1 preferentially bound to asparagine rich peptide substrates, as opposed to DnaK. Recombinant P. falciparum adenosylmethionine decarboxylase (PfAdoMetDC) co-expressed in E. coli with either KPf or PfHsp70-1 was produced as a fully folded product. Co-expression of PfAdoMetDC with heterologous DnaK in E. coli did not promote folding of the former. However, a combination of supplementary GroEL plus DnaK improved folding of PfAdoMetDC. These findings demonstrated that the SBD of PfHsp70-1 regulates several functional features of the protein and that this molecular chaperone is tailored to facilitate folding of plasmodial proteins.

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ALBERT, P., I. LACORREARESCALDINO, and B. TOUBLAN. "Study of nuclear basic proteins of Physarum polycephalum: Differential synthesis during plasmodial cell cycle and spherule germination." Cell Biology International Reports 16, no. 11 (1992): 1061–66. http://dx.doi.org/10.1016/s0309-1651(05)80030-x.

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Aguiar, Anna Caroline, Lorena R. F. de Sousa, Celia R. S. Garcia, Glaucius Oliva, and Rafael V. C. Guido. "New Molecular Targets and Strategies for Antimalarial Discovery." Current Medicinal Chemistry 26, no. 23 (October 10, 2019): 4380–402. http://dx.doi.org/10.2174/0929867324666170830103003.

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Malaria remains a major health problem, especially because of the emergence of resistant P. falciparum strains to artemisinin derivatives. In this context, safe and affordable antimalarial drugs are desperately needed. New proteins have been investigated as molecular targets for research and development of innovative compounds with welldefined mechanism of action. In this review, we highlight genetically and clinically validated plasmodial proteins as drug targets for the next generation of therapeutics. The enzymes described herein are involved in hemoglobin hydrolysis, the invasion process, elongation factors for protein synthesis, pyrimidine biosynthesis, post-translational modifications such as prenylation, phosphorylation and histone acetylation, generation of ATP in mitochondrial metabolism and aminoacylation of RNAs. Significant advances on proteomics, genetics, structural biology, computational and biophysical methods provided invaluable molecular and structural information about these drug targets. Based on this, several strategies and models have been applied to identify and improve lead compounds. This review presents the recent progresses in the discovery of antimalarial drug candidates, highlighting the approaches, challenges, and perspectives to deliver affordable, safe and low single-dose medicines to treat malaria.

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Babangida, S. M., G. J. Sow, and D. M. Shehu. "Antiplasmodial and haematological effects of Senna occidentalis leaf ethanolic extracts on Swiss albino mice infected with Plasmodium berghei." Bayero Journal of Pure and Applied Sciences 12, no. 2 (February 11, 2021): 122–28. http://dx.doi.org/10.4314/bajopas.v12i2.17.

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A research was conducted to investigate the haematological effects of ethanolic leaf extracts of Senna occidentalis on Swiss albino mice infected with 0.2 ml of Plasmodium berghei infected blood. Fifteen (15) mice weighing between 140-260g were assigned into five study groups of three mice each. The first group is treated with 0.2 mL of normal saline (drug free control). Group 2, 3, 4 were treated with 100, 200, and 400mg/kg of theethanolic leaf extract respectively while group 5 received 10mg/kg of chloroquine phosphate. All doses were administered orally. The results obtained were analyzed using Analysis of Variance with Duncan’s Multiple Range Test to separate the means. The result of the preliminary phytochemical analysis revealed the presence of alkaloids, saponins, cardiac glycosides, diterpenoids, flavonoids, steroids, tannins, Triterpenoids, carbohydrates and proteins. The level of parasite suppression ranges from 35% to 75% and the activity increased with increase in concentration of the extracts (dose dependent). The extracts were found to increase the level of some haematological parameters such as Red Blood Cells, White Blood Cells and Haemoglobin. The effect is concentration dependent, increases with increase in concentration. Thus, the anti plasmodial efficacy of the leaf extract of S. occidentalis on P. berghei is confirmed. It is recommended that , 400 mg/kg leaf ethanolic extracts of S. occidentalis couldbe use in the treatment of malarial fever.

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Chagot, Marie-Eve, Alexis Boutilliat, Alexandre Kriznik, and Marc Quinternet. "Structural Analysis of the Plasmodial Proteins ZNHIT3 and NUFIP1 Provides Insights into the Selectivity of a Conserved Interaction." Biochemistry 61, no. 7 (March 22, 2022): 479–93. http://dx.doi.org/10.1021/acs.biochem.1c00792.

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Selkirk, M. E., D. A. Denham, F. Partono, and R. M. Maizels. "Heat shock cognate 70 is a prominent immunogen in Brugian filariasis." Journal of Immunology 143, no. 1 (July 1, 1989): 299–308. http://dx.doi.org/10.4049/jimmunol.143.1.299.

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Abstract A cDNA expression library constructed from RNA derived from adult stage Brugia pahangi (mixed sexes) was screened with pooled sera from chronic, amicrofilaremic cases of human lymphatic filariasis from the Indonesian island of Tanjungpinang, where Brugia malayi is endemic. Polyclonal antisera raised to purified beta-galactosidase fusion proteins from two of the most highly reactive clones identified a protein of Mr 70,000 in all stages examined (microfilariae, L3 and adults) of both B. malayi and Brugia pahangi. Derivation of the amino acid sequence from these two overlapping cDNAs identified the encoded protein as a member of the heat shock protein 70 family, and showed the closest similarity to the constitutively expressed "heat shock cognate 70" (hsc70) protein. Hybridization of hsc70 cDNAs to RNA and DNA from B. pahangi under stringent conditions identified a major transcript of 2.4 kb and revealed the existence of a family of related genes. In vitro culture of larval stages of B. pahangi at elevated temperatures (43 degrees C) resulted in increased expression of hsc70, and a classic heat shock response in which five proteins (mr 18,500, 22,000, 62,000, 70,000, and 85,000) were exclusively synthesized in microfilariae. Analysis of cross-reactivities by Western blotting implied that antibody generated by infection with B. malayi was directed at filarial-specific determinants of Brugia hsc70. However, ELISA with recombinant fusion proteins for both Plasmodium falciparum and Schistosoma mansoni hsc70 indicated that some individuals with Brugian or Bancroftian filariasis did produce antibodies which cross-reacted with plasmodial and schistosomal homologs. Thus filarial-specific antibody responses were not generated in all individuals, indicating that this molecule would not be suitable for diagnostic purposes. ELISA with a purified beta-galactosidase fusion protein from B. pahangi showed antibody responses to hsc70 across the clinical spectrum of filariasis. Alignment of the derived amino acid sequences from B. pahangi, P. falciparum, S. mansoni and rat hsc70 homologs, and comparison of the immunologic reactivity of the products of the two cDNA clones by Western blotting and ELISA suggested that these determinants were located primarily at the C terminus of the protein.

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CHUA, CHUN-SONG, HUIYU LOW, and TIOW-SUAN SIM. "Co-chaperones of Hsp90 inPlasmodium falciparumand their concerted roles in cellular regulation." Parasitology 141, no. 9 (February 21, 2014): 1177–91. http://dx.doi.org/10.1017/s0031182013002084.

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SUMMARYCo-chaperones are well-known regulators of heat shock protein 90 (Hsp90). Hsp90 is a molecular chaperone that is essential in the eukaryotes for the folding and activation of numerous proteins involved in important cellular processes such as signal transduction, growth and developmental regulation. Co-chaperones assist Hsp90 in the protein folding process by modulating conformational changes to promote client protein interaction and functional maturation. With the recognition ofPlasmodium falciparumHsp90 (PfHsp90) as a potential antimalarial drug target, there is obvious interest in the study of its co-chaperones in their partnership in regulating cellular processes in malaria parasite. Previous studies on PfHsp90 have identified more than 10 co-chaperones inP. falciparumgenome. However, many of them remained annotated as putative proteins as their functionality has not been validated experimentally. So far, only five co-chaperones, PfHop, Pfp23, PfAha1, PfPP5 and PfFKBP35 have been characterized and shown to interact with PfHsp90. This review will summarize current knowledge on the co-chaperones inP. falciparumand discuss their regulatory roles on PfHsp90. As certain eukaryotic co-chaperones have also been implicated in altering the affinity of Hsp90 for its inhibitor, this review will also examine plasmodial co-chaperones’ potential influence on approaches towards designing antimalarials targeting PfHsp90.

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YEO, Hye-Jeong, Marie-Pierre LARVOR, Marie-Laure ANCELIN, and Henri J. VIAL. "Plasmodium falciparum CTP:phosphocholine cytidylyltransferase expressed in Escherichia coli: purification, characterization and lipid regulation." Biochemical Journal 324, no. 3 (June 15, 1997): 903–10. http://dx.doi.org/10.1042/bj3240903.

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The Plasmodium falciparum CTP:phosphocholine cytidylyltransferase (PfCCT) has been isolated from an overexpressing strain of Escherichia coli. The plasmid pETPfCCT mediated the overexpression of the full-length polypeptide directly. The recombinant protein corresponded to 6–9% of the total cellular proteins and was found essentially in the insoluble membrane fraction. Urea at 6 M was used to solubilize the recombinant protein from the insoluble fraction. The CCT activity was restored upon the removal of urea, and the protein was subsequently purified to homogeneity on a Q-Sepharose column. Approx. 1.4 mg of pure enzyme was obtained from a 250 ml culture of E. coli. Biochemical properties, including in vitro substrate specificity and enzymic characterization, were assessed. The lipid regulation of the recombinant plasmodial CCT activity was characterized for the first time. The Km values were 0.49±0.03 mM (mean±S.E.M.) for phosphocholine and 10.9±0.5 mM for CTP in the presence of lipid activators (oleic acid/egg phosphatidylcholine vesicles), whereas the Km values were 0.66±0.07 mM for phosphocholine and 28.9±0.8 mM for CTP in the absence of lipid activators. The PfCCT activity was stimulated to the same extent in response to egg phosphatidylcholine vesicles containing anionic lipids, such as oleic acid, cardiolipin and phosphatidylglycerol, and was insensitive or slightly sensitive to PC vesicles containing neutral lipids, such as diacylglycerol and monoacylglycerol. Furthermore, the stimulated enzyme activity by oleic acid was antagonized by the cationic aminolipid sphingosine. These lipid-dependence properties place the parasite enzyme intermediately between the mammalian enzymes and the yeast enzyme.

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Kampoun, Tanyaluck, Pimpisid Koonyosying, Jetsada Ruangsuriya, Parichat Prommana, Philip J. Shaw, Sumalee Kamchonwongpaisan, Hery Suwito, Ni Nyoman Tri Puspaningsih, Chairat Uthaipibull, and Somdet Srichairatanakool. "Antagonistic antimalarial properties of a methoxyamino chalcone derivative and 3-hydroxypyridinones in combination with dihydroartemisinin against Plasmodium falciparum." PeerJ 11 (April 27, 2023): e15187. http://dx.doi.org/10.7717/peerj.15187.

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Background The spread of artemisinin (ART)-resistant Plasmodium falciparum threatens the control of malaria. Mutations in the propeller domains of P. falciparum Kelch13 (k13) are strongly associated with ART resistance. Ferredoxin (Fd), a component of the ferredoxin/NADP+ reductase (Fd/FNR) redox system, is essential for isoprenoid precursor synthesis in the plasmodial apicoplast, which is important for K13-dependent hemoglobin trafficking and ART activation. Therefore, Fd is an antimalarial drug target and fd mutations may modulate ART sensitivity. We hypothesized that loss of Fd/FNR function enhances the effect of k13 mutation on ART resistance. Methods In this study, methoxyamino chalcone (C3), an antimalarial compound that has been reported to inhibit the interaction of recombinant Fd and FNR proteins, was used as a chemical inhibitor of the Fd/FNR redox system. We investigated the inhibitory effects of dihydroartemisinin (DHA), C3, and iron chelators including deferiprone (DFP), 1-(N-acetyl-6-aminohexyl)-3-hydroxy-2-methylpyridin-4-one (CM1) and deferiprone-resveratrol hybrid (DFP-RVT) against wild-type (WT), k13 mutant, fd mutant, and k13 fd double mutant P. falciparum parasites. Furthermore, we investigated the pharmacological interaction of C3 with DHA, in which the iron chelators were used as reference ART antagonists. Results C3 showed antimalarial potency similar to that of the iron chelators. As expected, combining DHA with C3 or iron chelators exhibited a moderately antagonistic effect. No differences were observed among the mutant parasites with respect to their sensitivity to C3, iron chelators, or the interactions of these compounds with DHA. Discussion The data suggest that inhibitors of the Fd/FNR redox system should be avoided as ART partner drugs in ART combination therapy for treating malaria.

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Devos, Sylvie, Kris Laukens, Peter Deckers, Dominique Van Der Straeten, Tom Beeckman, Dirk Inzé, Harry Van Onckelen, Erwin Witters, and Els Prinsen. "A Hormone and Proteome Approach to Picturing the Initial Metabolic Events During Plasmodiophora brassicae Infection on Arabidopsis." Molecular Plant-Microbe Interactions® 19, no. 12 (December 2006): 1431–43. http://dx.doi.org/10.1094/mpmi-19-1431.

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We report on the early response of Arabidopsis thaliana to the obligate biotrophic pathogen Plasmodiophora brassicae at the hormone and proteome level. Using a CYCB1;1::GUS construct, the re-initiation of infection-related cell division is shown from 4 days after inoculation on. Sensitivity to cytokinins and auxins as well as the endogenous hormone levels are evaluated. Both an enhanced cytokinin gene response and an accumulation of isopentenyl adenine and adenosine precede this re-initiation of cell division, whereas an enhanced auxin gene response is observed from 6 days after inoculation on. The alh1 mutant, impaired in the cross talk between ethylene and auxins, is resistant to P. brassicae. A differential protein analysis of infected versus noninfected roots and hypocotyls was performed using two-dimensional gel electrophoresis and quantitative image analysis, coupled to matrix-assisted laser desorption ionization time of flight-time of flight mass spectrometry-based protein identification. Of the visualized proteins, 12% show altered abundance compared with the nonin-fected plants, including proteins involved in metabolism, cell defense, cell differentiation, and detoxification. Combining the hormone and proteome data, we postulate that, at the very first stages of Plasmodiophora infection, plasmodial-produced cytokinins trigger a local re-initiation of cell division in the root cortex. Consequently, a de novo meristematic area is established that acts as a sink for host-derived indole-3-acetic acid, carbohydrates, nitrogen, and energy to maintain the pathogen and to trigger gall development.

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Sherman, I. W. "The Wellcome Trust Lecture: Mechanisms of molecular trafficking in malaria." Parasitology 96, S1 (January 1988): S57—S81. http://dx.doi.org/10.1017/s003118200008598x.

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SUMMARYThe asexual stages ofPlasmodiumliving within the erythrocyte result in growth-related changes in the permeability properties of the red cell for substances such as glucose, amino acids, purine nucleosides, sodium, potassium, calcium, zinc, iron and several antimalarial drugs such as chloroquine, amodiaquine and mefloquine. In most cases such changes do not appear to be due to a modification in the affinity or specificity of red cell transporters; indeed, for most substances the membrane-associated transporters are either unaffected or are partially inactivated. In malaria-infected erythrocytes, where a striking increase in influx has been observed, it has been attributed to the insertion of parasite-encoded transporters into the red cell membrane or the formation of aqueous leaks and/or pores. Leak formation, in the vast majority of cases, does not appear to be dependent on the insertion of plasmodial proteins into the red cell membrane. However, since the data presently available are less than satisfactory for discriminating amongst the various possible transport mechanisms future studies will require painstaking efforts and carefully controlled conditions to discriminate amongst the various transport systems which are operational in the malaria-infected red cell and the parasite.

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Kaly, Keïta, Sangaré Drissa, Berthé Brehima Boly, Tolo Nagou, Togo Mamadou, Mallé Mamadou, Traoré Abdoulaye Mamadou, et al. "The Hyper-Reactive Malarial Splenomegaly- A Rare and Severe Form of Chronic Plasmodial Infection: About A Case." Scholars Journal of Medical Case Reports 11, no. 06 (June 12, 2023): 1164–67. http://dx.doi.org/10.36347/sjmcr.2023.v11i06.031.

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Introduction: Hyper-reactive malarial splenomegaly is a leading cause of large tropical splenomegaly in endemic zones. Here, we report a case diagnosed in a young woman living in Guinea, a malaria-endemic area. Clinical observation: A 32-year-old Guinean woman with a history of repetitive malaria infection episodes presented to the internal medicine outpatient clinic with 5-months history of voluminous mass of the left flank extending to the umbilical region, with no pain and progressive onset, and a sensation of early satiety accompanied by eructation and epigastralgia worsened with eating. Digestive examination revealed a large, firm, smooth-surfaced, painless splenomegaly with a splenic size 20 centimeters below the left costal margin on the mid-clavicular line and measuring 28 centimeters in its long axis. The initial complete blood count showed a normocytic normochromic anemia with lymphocytosis, neutropenia and thrombocytopenia. The erythrocyte sedimentation rate (ESR) was 65 mm at the first hour. Malaria rapid diagnostic test (RDT) was positive for Plasmodium. The thick blood smear had come back negative. Serum protein electrophoresis demonstrated a decrease in albumin to 36.5 g/l and an increase in gamma globulins to 19.1 g/l. Immunoelectrophoresis of serum proteins showed a polyclonal increase in IgG. Abdominal ultrasound revealed enormous homogeneous splenomegaly (180 millimeters). The diagnosis of Hyper-reactive malarial splenomegaly was made on the basis of diagnostic criteria established by Fakunle et al in 1981. Our patient presented with enlarged splenomegaly, negative thick smear, positive RDT for plasmodium, elevated erythrocyte sedimentation rate, lymphocytosis, pancytopenia, and a good therapeutic response. Atovaquone-proguanil 250mg/100 mg at a dose of 1000mg/400 mg, i.e. 4 tablets taken as a single dose over three days, was initiated, then relayed by alternance of doxycycline 100 mg (100 mg once daily) for 1 month and nivaquine 100 mg ..........

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Arrey Tarkang, Protus, Achille Parfait Nwachiban Atchan, Jules-Roger Kuiate, Faith Apoelot Okalebo, Anastasia Nkatha Guantai, and Gabriel Agbor Agbor. "Antioxidant Potential of a Polyherbal Antimalarial as an Indicator of Its Therapeutic Value." Advances in Pharmacological Sciences 2013 (2013): 1–9. http://dx.doi.org/10.1155/2013/678458.

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Nefangis a polyherbal product composed ofMangifera indica(bark and leaf),Psidium guajava, Carica papaya, Cymbopogon citratus, Citrus sinensis, and Ocimum gratissimum(leaves), used for the treatment of malaria. Compounds with antioxidant activity are believed to modulate plasmodial infection. Antioxidant activity of the constituent aqueous plants extracts,in vitro, was evaluated using the 2,2-diphenyl-1-picrylhydrazyl (DPPH), total phenolic content (TPC), and ferric reducing antioxidant power (FRAP) methods and,in vivo,Nefang(100 and 500 mg kg−1) activity was evaluated in carbon tetrachloride-induced oxidative stressed Wistar rats. Superoxide dismutase, catalase activities, and lipid peroxidation by the malondialdehyde and total proteins assays were carried out.P. guajava, M. indicaleaf, and bark extracts had the highest antioxidant properties in all three assays, with no statistically significant difference. Rats treated with the carbon tetrachloride had a statistically significant decrease in levels of triglycerides, superoxide dismutase, and catalase (P<0.05) and increase in malondialdehyde activity, total protein levels, and liver and renal function markers, whereas rats treated withNefangshowed increased levels in the former and dose-dependent decrease towards normal levels in the later. These results reveal the constituent plants ofNefangthat contribute to itsin vivoantioxidant potential. This activity is a good indication of the therapeutic potential ofNefang.

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Sharma, Paresh, Kempaiah Rayavara, Daisuke Ito, Katherine Basore, and Sanjay A. Desai. "A CLAG3 Mutation in an Amphipathic Transmembrane Domain Alters Malaria Parasite Nutrient Channels and Confers Leupeptin Resistance." Infection and Immunity 83, no. 6 (April 13, 2015): 2566–74. http://dx.doi.org/10.1128/iai.02966-14.

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Erythrocytes infected with malaria parasites have increased permeability to ions and nutrients, as mediated by the plasmodial surface anion channel (PSAC) and recently linked to parasiteclag3genes. Although the encoded protein is integral to the host membrane, its precise contribution to solute transport remains unclear because it lacks conventional transmembrane domains and does not have homology to ion channel proteins in other organisms. Here, we identified a probable CLAG3 transmembrane domain adjacent to a variant extracellular motif. Helical-wheel analysis revealed strict segregation of polar and hydrophobic residues to opposite faces of a predicted α-helical transmembrane domain, suggesting that the domain lines a water-filled pore. A single CLAG3 mutation (A1210T) in a leupeptin-resistant PSAC mutant falls within this transmembrane domain and may affect pore structure. Allelic-exchange transfection and site-directed mutagenesis revealed that this mutation alters solute selectivity in the channel. The A1210T mutation also reduces the blocking affinity of PSAC inhibitors that bind on opposite channel faces, consistent with global changes in channel structure. Transfected parasites carrying this mutation survived a leupeptin challenge significantly better than a transfection control did. Thus, the A1210T mutation contributes directly to both altered PSAC activity and leupeptin resistance. These findings reveal the molecular basis of a novel antimalarial drug resistance mechanism, provide a framework for determining the channel's composition and structure, and should guide the development of therapies targeting the PSAC.

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Niyibizi, Jean Baptiste, Peter G. Kirira, Francis T. Kimani, Fiona Oyatsi, and Joseph K. Ng’ang’a. "Chemical Synthesis, Efficacy, and Safety of Antimalarial Hybrid Drug Comprising of Sarcosine and Aniline Pharmacophores as Scaffolds." Journal of Tropical Medicine 2020 (April 9, 2020): 1–12. http://dx.doi.org/10.1155/2020/1643015.

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Malaria is a disease caused by protozoans transmitted to humans by infected female Anopheles mosquitoes. According to the WHO report of 2015, there were 214 million cases of malaria with 438,000 deaths worldwide. Ninety percent of world’s malaria cases occur in Africa, where the disease is recognized as a serious impediment to economic and social development. Despite advancement in malaria research, the disease continues to be a global problem, especially in developing countries. Currently, there is no effective vaccine for malaria control. In addition, although there are effective drugs for treatment of malaria, this could be lost to the drug resistance in different Plasmodium species. The most lethal form is caused by P. falciparum which has developed resistance to many chemotherapeutic agents and possibly to the current drugs of choice. Reducing the impact of malaria is a key to achieving the sustainable development goals which are geared toward combating the disease. Covalent bitherapy is a rational and logical way of drug design which entails joining a couple of molecules with individual intrinsic action into a unique agent, hence packaging dual activity into one hybrid. This suggests the need to develop new antimalarial drugs that are effective against malaria parasites based on the new mode of action, molecular targets, and chemical structures. In silico studies have shown that sarcosine is able to bind to unique plasmodia proteins (P. falciparum ATCase), whereas aniline can be a ligand to target protein (enoyl acyl carrier protein reductase), hence suppressing the progression of the disease. The main objective of this study was to synthesize and determine the efficacy and safety of antiplasmodial hybrid drug comprising the sarcosine and aniline derivative for management of plasmodial infections. The hybrid drug was synthesized by adding thionyl chloride to sarcosine to form acyl chloride which was then added to aniline to form sarcosine-aniline hybrid molecule. The IC50 of sarcosine-aniline hybrid was 44.80 ± 4.70 ng/ml compared with that of aniline derivative which was 22.86 ± 1.26 ng/ml. The IC50 of control drugs was 2.63 ± 0.38 ng/ml and 5.69 ± 0.39 ng/ml for artesunate and chloroquine, respectively. There was a significant difference between IC50 of sarcosine-aniline hybrid and aniline derivative (p<0.05). There was also a significant difference between sarcosine-aniline hybrid and standard drugs used to treat malaria including artesunate and chloroquine (p<0.05). The ED50 of sarcosine-aniline hybrid drug was 6.49 mg/kg compared with that of aniline derivative which was 3.61 mg/kg. The ED50 of control drugs was 3.56 mg/kg, 2.94 mg/kg, and 1.78 mg/kg for artesunate-aniline hybrid, artesunate, and chloroquine, respectively. There was a significant difference (p<0.05) between ED50 of sarcosine-aniline hybrid and both controls such as aniline derivative, artesunate, artesunate-aniline hybrid, and chloroquine. Cytotoxicity results revealed that sarcosine-aniline hybrid was safe to vero cells with a CC50 of 50.18 ± 3.53 μg/ml. Sarcosine-aniline hybrid was significantly less toxic compared with artesunate, chloroquine, and doxorubicin. Sarcosine-aniline hybrid was efficacious and safe to mice. Therefore, covalent bitherapy should be used in drug development for drug resistance mitigation.

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Bushkin, G. Guy, Daniel M. Ratner, Jike Cui, Sulagna Banerjee, Manoj T. Duraisingh, Cameron V. Jennings, Jeffrey D. Dvorin, et al. "Suggestive Evidence for Darwinian Selection against Asparagine-Linked Glycans of Plasmodium falciparum and Toxoplasma gondii." Eukaryotic Cell 9, no. 2 (September 25, 2009): 228–41. http://dx.doi.org/10.1128/ec.00197-09.

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ABSTRACT We are interested in asparagine-linked glycans (N-glycans) of Plasmodium falciparum and Toxoplasma gondii, because their N-glycan structures have been controversial and because we hypothesize that there might be selection against N-glycans in nucleus-encoded proteins that must pass through the endoplasmic reticulum (ER) prior to threading into the apicoplast. In support of our hypothesis, we observed the following. First, in protists with apicoplasts, there is extensive secondary loss of Alg enzymes that make lipid-linked precursors to N-glycans. Theileria makes no N-glycans, and Plasmodium makes a severely truncated N-glycan precursor composed of one or two GlcNAc residues. Second, secreted proteins of Toxoplasma, which uses its own 10-sugar precursor (Glc3Man5GlcNAc2) and the host 14-sugar precursor (Glc3Man9GlcNAc2) to make N-glycans, have very few sites for N glycosylation, and there is additional selection against N-glycan sites in its apicoplast-targeted proteins. Third, while the GlcNAc-binding Griffonia simplicifolia lectin II labels ER, rhoptries, and surface of plasmodia, there is no apicoplast labeling. Similarly, the antiretroviral lectin cyanovirin-N, which binds to N-glycans of Toxoplasma, labels ER and rhoptries, but there is no apicoplast labeling. We conclude that possible selection against N-glycans in protists with apicoplasts occurs by eliminating N-glycans (Theileria), reducing their length (Plasmodium), or reducing the number of N-glycan sites (Toxoplasma). In addition, occupation of N-glycan sites is markedly reduced in apicoplast proteins versus some secretory proteins in both Plasmodium and Toxoplasma.

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Crowther, Gregory J., Alberto J. Napuli, Andrew P. Thomas, Diana J. Chung, Kuzma V. Kovzun, David J. Leibly, Lisa J. Castaneda, et al. "Buffer Optimization of Thermal Melt Assays of Plasmodium Proteins for Detection of Small-Molecule Ligands." Journal of Biomolecular Screening 14, no. 6 (May 21, 2009): 700–707. http://dx.doi.org/10.1177/1087057109335749.

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In the past decade, thermal melt/thermal shift assays have become a common tool for identifying ligands and other factors that stabilize specific proteins. Increased stability is indicated by an increase in the protein's melting temperature (Tm). In optimizing the assays for subsequent screening of compound libraries, it is important to minimize the variability of Tm measurements so as to maximize the assay's ability to detect potential ligands. The authors present an investigation of Tm variability in recombinant proteins from Plasmodium parasites. Ligands of Plasmodium proteins are particularly interesting as potential starting points for drugs for malaria, and new drugs are urgently needed. A single standard buffer (100 mM HEPES [pH 7.5], 150 mM NaCl) permitted estimation of Tm for 58 of 61 Plasmodium proteins tested. However, with several proteins, Tm could not be measured with a consistency suitable for high-throughput screening unless alternative protein-specific buffers were employed. The authors conclude that buffer optimization to minimize variability in Tm measurements increases the success of thermal melt screens involving proteins for which a standard buffer is suboptimal. ( Journal of Biomolecular Screening 2009:700-707)

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Ahmad, Moaz, and Renu Tuteja. "Plasmodium falciparumRuvB proteins." Communicative & Integrative Biology 5, no. 4 (July 2012): 350–61. http://dx.doi.org/10.4161/cib.20005.

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Pihlajamaa, Tero, Tommi Kajander, Juho Knuuti, Kaisa Horkka, Amit Sharma, and Perttu Permi. "Structure of Plasmodium falciparum TRAP (thrombospondin-related anonymous protein) A domain highlights distinct features in apicomplexan von Willebrand factor A homologues." Biochemical Journal 450, no. 3 (February 28, 2013): 469–76. http://dx.doi.org/10.1042/bj20121058.

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TRAP (thrombospondin-related anonymous protein), localized in the micronemes and on the surface of sporozoites of the notorious malaria parasite Plasmodium, is a key molecule upon infection of mammalian host hepatocytes and invasion of mosquito salivary glands. TRAP contains two adhesive domains responsible for host cell recognition and invasion, and is known to be essential for infectivity. In the present paper, we report high-resolution crystal structures of the A domain of Plasmodium falciparum TRAP with and without bound Mg2+. The structure reveals a vWA (von Willebrand factor A)-like fold and a functional MIDAS (metal-ion-dependent adhesion site), as well as a potential heparan sulfate-binding site. Site-directed mutagenesis and cell-attachment assays were used to investigate the functional roles of the surface epitopes discovered. The reported structures are the first determined for a complete vWA domain of parasitic origin, highlighting unique features among homologous domains from other proteins characterized hitherto. Some of these are conserved among Plasmodiae exclusively, whereas others may be common to apicomplexan organisms in general.

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Singh, Ajay, K. Jordan Walker, Puran S. Sijwali, Anthony L. Lau, and Philip J. Rosenthal. "A chimeric cysteine protease of Plasmodium berghei engineered to resemble the Plasmodium falciparum protease falcipain-2." Protein Engineering, Design and Selection 20, no. 4 (January 1, 2007): 171–77. http://dx.doi.org/10.1093/protein/gzm009.

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Goh, Carlmond Kah Wun, Jovi Silvester, Wan Nur Shuhaida Wan Mahadi, Lee Ping Chin, Lau Tiek Ying, Thean Chor Leow, Ryo Kurahashi, Kazufumi Takano, and Cahyo Budiman. "Expression and characterization of functional domains of FK506-binding protein 35 from Plasmodium knowlesi." Protein Engineering, Design and Selection 31, no. 12 (December 1, 2018): 489–98. http://dx.doi.org/10.1093/protein/gzz008.

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Abstract The FK506-binding protein of Plasmodium knowlesi (Pk-FKBP35) is considerably a viable antimalarial drug target, which belongs to the peptidyl-prolyl cis-trans isomerase (PPIase) protein family member. Structurally, this protein consists of an N-terminal FK506-binding domain (FKBD) and a C-terminal tetratricopeptide repeat domain (TPRD). This study aims to decipher functional properties of these domains as a platform for development of novel antimalarial drugs. Accordingly, full-length Pk-FKBP35 as well as its isolated domains, Pk-FKBD and Pk-TPRD were overexpressed, purified, and characterized. The results showed that catalytic PPIase activity was confined to the full-length Pk-FKBP35 and Pk-FKBD, suggesting that the catalytic activity is structurally regulated by the FKBD. Meanwhile, oligomerization analysis revealed that Pk-TPRD is essential for dimerization. Asp55, Arg60, Trp77 and Phe117 in the Pk-FKBD were considerably important for catalysis as underlined by significant reduction of PPIase activity upon mutations at these residues. Further, inhibition activity of Pk-FKBP35 towards calcineurin phosphatase activity revealed that the presence of FKBD is essential for the inhibitory property, while TPRD may be important for efficient binding to calcineurin. We then discussed possible roles of FKBP35 in Plasmodium cells and proposed mechanisms by which the immunosuppressive drug, FK506, interacts with the protein.

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Temporão, Adriana, Margarida Sanches-Vaz, Rafael Luís, Helena Nunes-Cabaço, Terry K. Smith, Miguel Prudêncio, and Luisa M. Figueiredo. "Excreted Trypanosoma brucei proteins inhibit Plasmodium hepatic infection." PLOS Neglected Tropical Diseases 15, no. 10 (October 29, 2021): e0009912. http://dx.doi.org/10.1371/journal.pntd.0009912.

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Malaria, a disease caused by Plasmodium parasites, remains a major threat to public health globally. It is the most common disease in patients with sleeping sickness, another parasitic illness, caused by Trypanosoma brucei. We have previously shown that a T. brucei infection impairs a secondary P. berghei liver infection and decreases malaria severity in mice. However, whether this effect requires an active trypanosome infection remained unknown. Here, we show that Plasmodium liver infection can also be inhibited by the serum of a mouse previously infected by T. brucei and by total protein lysates of this kinetoplastid. Biochemical characterisation showed that the anti-Plasmodium activity of the total T. brucei lysates depends on its protein fraction, but is independent of the abundant variant surface glycoprotein. Finally, we found that the protein(s) responsible for the inhibition of Plasmodium infection is/are present within a fraction of ~350 proteins that are excreted to the bloodstream of the host. We conclude that the defence mechanism developed by trypanosomes against Plasmodium relies on protein excretion. This study opens the door to the identification of novel antiplasmodial intervention strategies.

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Sojka, Daniel, Marie Jalovecká, and Jan Perner. "Babesia, Theileria, Plasmodium and Hemoglobin." Microorganisms 10, no. 8 (August 15, 2022): 1651. http://dx.doi.org/10.3390/microorganisms10081651.

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The Propagation of Plasmodium spp. and Babesia/Theileria spp. vertebrate blood stages relies on the mediated acquisition of nutrients available within the host’s red blood cell (RBC). The cellular processes of uptake, trafficking and metabolic processing of host RBC proteins are thus crucial for the intraerythrocytic development of these parasites. In contrast to malarial Plasmodia, the molecular mechanisms of uptake and processing of the major RBC cytoplasmic protein hemoglobin remain widely unexplored in intraerythrocytic Babesia/Theileria species. In the paper, we thus provide an updated comparison of the intraerythrocytic stage feeding mechanisms of these two distantly related groups of parasitic Apicomplexa. As the associated metabolic pathways including proteolytic degradation and networks facilitating heme homeostasis represent attractive targets for diverse antimalarials, and alterations in these pathways underpin several mechanisms of malaria drug resistance, our ambition is to highlight some fundamental differences resulting in different implications for parasite management with the potential for novel interventions against Babesia/Theileria infections.

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Krzych, U., J. A. Lyon, T. Jareed, I. Schneider, M. R. Hollingdale, D. M. Gordon, and W. R. Ballou. "T lymphocytes from volunteers immunized with irradiated Plasmodium falciparum sporozoites recognize liver and blood stage malaria antigens." Journal of Immunology 155, no. 8 (October 15, 1995): 4072–77. http://dx.doi.org/10.4049/jimmunol.155.8.4072.

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Abstract The model of protective immunity induced by immunization with irradiated plasmodia sporozoites (SPZ) has become the prototype for a promising vaccine strategy based on Ab and CTL responses directed against pre-erythrocytic stage Ags, in particular the circumsporozoite protein (CSP) and sporozoite surface protein 2 (SSP2). However, results from recently conducted vaccine studies suggest that T cell responses directed against additional specificities might also be required for protection. We have tested this hypothesis by examining human T lymphocytes from irradiated Plasmodium falciparum SPZ-immune volunteers for proliferative reactivities to parasitized red blood cells (pRBC) and recombinant proteins and synthetic peptides representing certain liver and blood stage Ags. In this work, we report that although SPZ-induced protective immunity is stage-specific, SPZ-immune lymphocytes recognized determinants associated with erythrocytic and liver stage parasites. Thus, protective immunity induced by irradiated SPZ may depend upon responses against pre-erythrocytic Ags in addition to CSP and SSP2.

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Parr-Vasquez, C. L., and R. Y. Yada. "Functional chimera of porcine pepsin prosegment and Plasmodium falciparum plasmepsin II." Protein Engineering Design and Selection 23, no. 1 (November 12, 2009): 19–26. http://dx.doi.org/10.1093/protein/gzp066.

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Hewitt, C. O., R. B. Sessions, T. R. Dafforn, and J. J. Holbrook. "Protein engineering tests of a homology model of Plasmodium falciparum lactate dehydrogenase." Protein Engineering Design and Selection 10, no. 1 (January 1, 1997): 39–44. http://dx.doi.org/10.1093/protein/10.1.39.

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Gavigan, Clare S., Senan P. Kiely, Jocelyne Hirtzlin, and Angus Bell. "Cyclosporin-binding proteins of Plasmodium falciparum." International Journal for Parasitology 33, no. 9 (August 2003): 987–96. http://dx.doi.org/10.1016/s0020-7519(03)00125-5.

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Hughes, Marianne K., and Austin L. Hughes. "Natural selection on Plasmodium surface proteins." Molecular and Biochemical Parasitology 71, no. 1 (April 1995): 99–113. http://dx.doi.org/10.1016/0166-6851(95)00037-2.

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Taylor, Helen M., Tony Triglia, Jenny Thompson, Mohammed Sajid, Ruth Fowler, Mark E. Wickham, Alan F. Cowman, and Anthony A. Holder. "Plasmodium falciparum Homologue of the Genes for Plasmodium vivax and Plasmodium yoeliiAdhesive Proteins, Which Is Transcribed but Not Translated." Infection and Immunity 69, no. 6 (June 1, 2001): 3635–45. http://dx.doi.org/10.1128/iai.69.6.3635-3645.2001.

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ABSTRACT The 235-kDa family of rhoptry proteins in Plasmodium yoelii and the two reticulocyte binding proteins of P. vivax comprise a family of proteins involved in host cell selection and erythrocyte invasion. Here we described a member of the gene family found in P. falciparum (PfRH3) that is transcribed in its entirety, under stage-specific control, with correct splicing of the intron, but appears not to be translated, probably due to two reading frameshifts at the 5′ end of the gene.

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Xiao, H., T. Tanaka, M. Ogawa, and R. Y. Yada. "Expression and enzymatic characterization of the soluble recombinant plasmepsin I from Plasmodium falciparum." Protein Engineering Design and Selection 20, no. 12 (November 22, 2007): 625–33. http://dx.doi.org/10.1093/protein/gzm066.

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Journal articles on the topic 'Plasmodial Proteins'

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