11 results on '"Karine G Le Roch"'
Search Results
2. Synthesis and preliminary biological evaluation of a small library of hybrid compounds based on Ugi isocyanide multicomponent reactions with a marine natural product scaffold
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Abimael D. Rodríguez, Alejandro M. S. Mayer, Jacques Prudhomme, Karine G. Le Roch, Scott G. Franzblau, Edward Avilés, and Kevin Chandrasena
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Stereochemistry ,Antiparasitic ,medicine.drug_class ,Ugi multicomponent reaction ,Medicinal & Biomolecular Chemistry ,Isocyanide ,Plasmodium falciparum ,Clinical Biochemistry ,Anti-Inflammatory Agents ,Pharmaceutical Science ,Microbial Sensitivity Tests ,medicine.disease_cause ,Biochemistry ,Article ,Small Molecule Libraries ,Medicinal and Biomolecular Chemistry ,Inhibitory Concentration 50 ,chemistry.chemical_compound ,Rare Diseases ,Drug Discovery ,medicine ,Tuberculosis ,Amines ,Cytotoxicity ,Natural product hybridization ,Molecular Biology ,Escherichia coli ,Cyanides ,Natural product ,Molecular Structure ,Superoxide ,Organic Chemistry ,Pharmacology and Pharmaceutical Sciences ,Mycobacterium tuberculosis ,Combinatorial chemistry ,In vitro ,Malaria ,Orphan Drug ,Infectious Diseases ,Good Health and Well Being ,chemistry ,Quinolines ,Molecular Medicine ,Pharmacophore ,Anti-neuroinflammatory activity - Abstract
A mixture-based combinatorial library of five Ugi adducts (4-8) incorporating known antitubercular and antimalarial pharmacophores was successfully synthesized, starting from the naturally occurring diisocyanide 3, via parallel Ugi four-center three-component reactions (U-4C-3CR). The novel α-acylamino amides obtained were evaluated for their antiinfective potential against laboratory strains of Mycobacterium tuberculosis H37Rv and chloroquine-susceptible 3D7 Plasmodium falciparum. Interestingly, compounds 4-8 displayed potent in vitro antiparasitic activity with higher cytotoxicity in comparison to their diisocyanide precursor 3, with the best compound exhibiting an IC50 value of 3.6 nM. Additionally, these natural product inspired hybrids potently inhibited in vitro thromboxane B2 (TXB2) and superoxide anion (O2(-)) generation from Escherichia coli lipopolysaccharide (LPS)-activated rat neonatal microglia, with concomitant low short-term toxicity.
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- 2015
3. Structures, semisyntheses, and absolute configurations of the antiplasmodial α-substituted β-lactam monamphilectines B and C from the sponge Svenzea flava
- Author
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Abimael D. Rodríguez, Jacques Prudhomme, Karine G. Le Roch, and Edward Avilés
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Stereochemistry ,Ugi multicomponent reaction ,Isocyanide ,beta-Lactams ,Ring (chemistry) ,Biochemistry ,Article ,Medicinal and Biomolecular Chemistry ,chemistry.chemical_compound ,Rare Diseases ,Drug Discovery ,Organic chemistry ,West coast ,Monamphilectines ,biology ,Drug discovery ,Organic Chemistry ,Svenzea flava ,β-lactams ,Chemical data ,Plasmodium falciparum ,biology.organism_classification ,Chemical correlation ,Malaria ,Vector-Borne Diseases ,Sponge ,Good Health and Well Being ,chemistry ,Lactam - Abstract
Bioassay-guided fractionation of the Caribbean sponge Svenzea flava collected near Mona Island, off the west coast of Puerto Rico, led to the isolation of two isocyanide amphilectane-type diterpenes named monamphilectines B and C (2 and 3). Attached to the backbone of each of these compounds is the first α-substituted monocyclic β-lactam ring to be isolated from a marine organism. The molecular structures of 2 and 3 were established by spectroscopic methods and then confirmed unequivocally by chemical correlation and comparison of physical and chemical data with the natural products. The new β-lactams were successfully synthesized in one step, starting from the known diisocyanide 4, via parallel Ugi four-center three-component reactions (U-4C-3CR) that also established their absolute stereostructures. Interestingly, compounds 2 and 3 exhibited activities in the low nanomolar range against the human malaria parasite Plasmodium falciparum.
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- 2015
4. Recent advances in malaria drug discovery
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Jutta Wanner, Karine G. Le Roch, and Marco A. Biamonte
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Plasmodium ,medicine.medical_specialty ,medicine.medical_treatment ,Clinical Biochemistry ,Pharmaceutical Science ,Antimalarial ,Review ,Disease ,Liver transplantation ,Biology ,01 natural sciences ,Biochemistry ,Article ,Antimalarials ,03 medical and health sciences ,Drug Discovery ,medicine ,Animals ,Humans ,Intensive care medicine ,Molecular Biology ,030304 developmental biology ,Liver stage ,0303 health sciences ,Molecular Structure ,010405 organic chemistry ,Transmission (medicine) ,Drug discovery ,Extramural ,Organic Chemistry ,Drugs ,medicine.disease ,Liver Transplantation ,Malaria ,3. Good health ,0104 chemical sciences ,Blood stage ,Liver ,Immunology ,Molecular Medicine - Abstract
This digest covers some of the most relevant progress in malaria drug discovery published between 2010 and 2012. There is an urgent need to develop new antimalarial drugs. Such drugs can target the blood stage of the disease to alleviate the symptoms, the liver stage to prevent relapses, and the transmission stage to protect other humans. The pipeline for the blood stage is becoming robust, but this should not be a source of complacency, as the current therapies set a high standard. Drug discovery efforts directed towards the liver and transmission stages are in their infancy but are receiving increasing attention as targeting these stages could be instrumental in eradicating malaria.
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- 2013
- Full Text
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5. Nucleosome occupancy at transcription start sites in the human malaria parasite: A hard-wired evolution of virulence?
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Stefano Lonardi, Elena Y. Harris, Karine G. Le Roch, Nadia Ponts, University of California [Riverside] (UCR), and University of California
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Microbiology (medical) ,5' Flanking Region ,[SDV]Life Sciences [q-bio] ,Plasmodium falciparum ,Microbiology ,Article ,Open Reading Frames ,03 medical and health sciences ,0302 clinical medicine ,Genetics ,Humans ,Nucleosome ,3' Flanking Region ,Promoter Regions, Genetic ,Molecular Biology ,Gene ,Ecology, Evolution, Behavior and Systematics ,030304 developmental biology ,Regulation of gene expression ,0303 health sciences ,Models, Genetic ,Virulence ,biology ,Gene Expression Profiling ,Computational Biology ,Promoter ,biology.organism_classification ,Biological Evolution ,Chromatin ,Nucleosomes ,3. Good health ,Gene expression profiling ,Infectious Diseases ,Gene Expression Regulation ,FAIRE-Seq ,Transcription Initiation Site ,Genome, Protozoan ,030217 neurology & neurosurgery - Abstract
International audience; Almost a decade after the publication of the complete sequence of the genome of the human malaria parasite Plasmodium falciparum, the mechanisms involved in gene regulation remain poorly understood. Like other eukaryotic organisms, P. falciparum's genomic DNA organizes into nucleosomes. Nucleosomes are the basic structural units of eukaryotic chromatin and their regulation is known to play a key role in regulation of gene expression. Despite its importance, the relationship between nucleosome positioning and gene regulation in the malaria parasite has only been investigated recently. Using two independent and complementary techniques followed by next-generation high-throughput sequencing, our laboratory recently generated a dynamic atlas of nucleosome-bound and nucleosome-free regions (NFRs) at single-nucleotide resolution throughout the parasite erythrocytic cycle. We have found evidences that genome-wide changes in nucleosome occupancy play a critical role in controlling the rigorous parasite replication in infected red blood cells. However, the role of nucleosome positioning at remarkable locations such as transcriptional start sites (TSS) was not investigated. Here we show that a study of NFR in experimentally determined TSS and in silico-predicted promoters can provide deeper insights of how a transcriptionally permissive organization of chromatin can control the parasite's progression through its life cycle. We find that NFRs found at TSS and core promoters are strongly associated with high levels of gene expression in asexual erythrocytic stages, whereas nucleosome-bound TSSs and promoters are associated with silent genes preferentially expressed in sexual stages. The implications in terms of regulatory evolution, adaptation of gene expression and their impact in the design of antimalarial strategies are discussed.
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- 2011
6. Unusual antimalarial meroditerpenes from tropical red macroalgae
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William G.L. Aalbersberg, Jacques Prudhomme, Julia Kubanek, Craig R. Fairchild, Scott G. Franzblau, Mark E. Hay, Karine G. Le Roch, and E. Paige Stout
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Circular dichroism ,Stereochemistry ,Plasmodium falciparum ,Clinical Biochemistry ,Pharmaceutical Science ,Biochemistry ,Article ,Apicomplexa ,Antimalarials ,chemistry.chemical_compound ,Drug Discovery ,Humans ,Phenols ,Molecular Biology ,Natural product ,biology ,Circular Dichroism ,Organic Chemistry ,Absolute configuration ,Seaweed ,biology.organism_classification ,Terpenoid ,chemistry ,Molecular Medicine ,Diterpenes ,Diterpene - Abstract
Three antimalarial meroditerpenes have been isolated from two Fijian red macroalgae. The absolute stereochemistry of callophycolide A (1), a unique macrolide from Callophycus serratus, was determined using a combination of Mosher's ester analysis, circular dichroism analysis with a dimolybdenum tetraacetate complex, and conformational analysis using NOEs. In addition, two known tocopherols, β-tocopherylhydroquinone (4) and δ-tocopherylhydroquinone (5), were isolated from Amphiroa crassa. By oxidizing 5 to the corresponding δ-tocopherylquinone (6), antimalarial activity against the human malaria parasite Plasmodium falciparum was increased by more than 20-fold.
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- 2010
7. Antineoplastic unsaturated fatty acids from Fijian macroalgae
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Julia Kubanek, Mark E. Hay, Jacques Prudhomme, Karine G. Le Roch, Craig R. Fairchild, William G.L. Aalbersberg, and Ren-Wang Jiang
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Magnetic Resonance Spectroscopy ,Cell Survival ,Stereochemistry ,Chemical structure ,Plasmodium falciparum ,Antineoplastic Agents ,Plant Science ,Horticulture ,Conjugated system ,Biology ,Biochemistry ,Article ,Antimalarials ,Inhibitory Concentration 50 ,Glycolipid ,Chlorophyta ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Molecular Biology ,Unsaturated fatty acid ,Molecular Structure ,Biological activity ,General Medicine ,Nuclear magnetic resonance spectroscopy ,Mechanism of action ,Rhodophyta ,Fatty Acids, Unsaturated ,lipids (amino acids, peptides, and proteins) ,Glycolipids ,medicine.symptom ,Two-dimensional nuclear magnetic resonance spectroscopy - Abstract
Phytochemical analysis of Fijian populations of the green alga Tydemania expeditionis led to the isolation of two unsaturated fatty acids, 3(zeta)-hydroxy-octadeca-4(E),6(Z),15(Z)-trienoic acid (1) and 3(zeta)-hydroxy-hexadeca-4(E),6(Z)-dienoic acid (2), along with the known 3(zeta)-hydroxy-octadeca-4(E),6(Z)-dienoic acid (4). Investigations of the red alga Hydrolithon reinboldii led to identification of a glycolipid, lithonoside (3), and five known compounds, 15-tricosenoic acid, hexacosa-5,9-dienoic methyl ester, beta-sitosterol, 10(S)-hydroxypheophytin A, and 10(R)-hydroxypheophytin A. The structures of 1-3 were elucidated by spectroscopic methods (1D and 2D NMR spectroscopy and ESI-MS). Compounds 1, 2, and 4, containing conjugated double bonds, demonstrated moderate inhibitory activity against a panel of tumor cell lines (including breast, colon, lung, prostate and ovarian cells) with IC(50) values ranging from 1.3 to 14.4 microM. The similar cell selectivity patterns of these three compounds suggest that they might act by a common, but unknown, mechanism of action.
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- 2008
8. Regulatory motifs uncovered among gene expression clusters in Plasmodium falciparum
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Alissa Myrick, Carolyn K. Dong, Karine G. Le Roch, Dyann F. Wirth, Jennifer S. Sims, Elizabeth A. Winzeler, Todd Gierahn, Kevin T. Militello, and Anusha Gunasekera
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Genetics ,Regulation of gene expression ,Base Sequence ,Five prime untranslated region ,Gene Expression Profiling ,Genes, Protozoan ,Plasmodium falciparum ,Eukaryotic transcription ,Chloroquine ,Promoter ,DNA, Protozoan ,Biology ,Transfection ,Gene expression profiling ,Antimalarials ,Protein Subunits ,Gene Expression Regulation ,Multigene Family ,Gene expression ,Animals ,Parasitology ,Sequence motif ,Molecular Biology ,Gene ,Oligonucleotide Array Sequence Analysis - Abstract
Control of gene expression is poorly understood in the Plasmodium system, where relatively few homologues to known eukaryotic transcription factors have been uncovered. Recent evidence suggests that the parasite may utilize a combinatorial mode of gene regulation, with multiple cis-acting sequences contributing to overall activity at individual promoters [1]. To further probe this mechanism of control, we first searched for over-represented sequence motifs among gene clusters sharing similar expression profiles in Plasmodium falciparum. More specifically, we applied bioinformatic tools to a previously characterized micro-array data set from drug-treated asexual stage cultures (Gunasekera et al., submitted). Cluster analysis of 600 drug responsive genes identified only a single 5' motif, GAGAGAA. Two additional 5' motifs, ACTATAAAGA and TGCAC, were also shared among loci displaying patterns of coordinate expression across varying asexual growth stages. Secondly and most importantly, the functional relevance of each motif was tested in two independent assays-transient transfection and gel-retardation experiments. The GAGAGAA and TGCAC motifs were both active in the former. The GAGAGAA and ACTATAAAGA elements formed specific RNA-protein, but not DNA-protein complexes in gel shift assays, suggesting a key level of control at the RNA level. This is the first report of functionally characterized motifs in P. falciparum that were uncovered following clustering analysis of its asexual stage transcriptome. Together, both the bioinformatic and functional data reported here imply that multiple forms of gene regulation, including post-transcriptional control, may be important in the malarial system.
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- 2007
9. The Plasmodium falciparum sexual development transcriptome: A microarray analysis using ontology-based pattern identification
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Peter L. Blair, Yingyao Zhou, Karine G. Le Roch, Jason A. Young, Quinton L. Fivelman, Patricia de la Vega, Daniel J. Carucci, Elizabeth A. Winzeler, and David A. Baker
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Male ,Genetics ,Base Sequence ,Transcription, Genetic ,Microarray ,Microarray analysis techniques ,Gene Expression Profiling ,Plasmodium falciparum ,Sequence alignment ,DNA, Protozoan ,Biology ,Transcriptome ,Gene expression profiling ,Multigene Family ,Transcriptional regulation ,Animals ,Female ,Parasitology ,Identification (biology) ,Sexual Maturation ,Genome, Protozoan ,Sequence Alignment ,Molecular Biology ,Gene ,Oligonucleotide Array Sequence Analysis - Abstract
The sexual stages of malarial parasites are essential for the mosquito transmission of the disease and therefore are the focus of transmissionblocking drug and vaccine development. In order to better understand genes important to the sexual development process, the transcriptomes of high-purity stage I–V Plasmodium falciparumgametocytes were comprehensively profiled using a full-genome high-density oligonucleotide microarray. The interpretation of this transcriptional data was aided by applying a novel knowledge-based data-mining algorithm termed ontology-based pattern identification (OPI) using current information regarding known sexual stage genes as a guide. This analysis resulted in the identification of a sexual development cluster containing 246 genes, of which ∼75% were hypothetical, exhibiting highly-correlated, gametocyte-specific expression patterns. Inspection of the upstream promoter regions of these 246 genes revealed putative cis-regulatory elements for sexual development transcriptional control mechanisms. Furthermore, OPI analysis was extended using current annotations provided by the Gene Ontology Consortium to identify 380 statistically significant clusters containing genes with expression patterns characteristic of various biological processes, cellular components, and molecular functions. Collectively, these results, available as part of a web-accessible OPI database (http://carrier.gnf.org/publications/Gametocyte ), shed light on the components of molecular mechanisms underlying parasite sexual development and other areas of malarial parasite biology. © 2005 Elsevier B.V. All rights reserved.
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- 2005
10. Influence of Human p16INK4 and p21CIP1 on the in Vitro Activity of Recombinant Plasmodium falciparum Cyclin-Dependent Protein Kinases
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Jeanne A. Geyer, James Koh, Sean T. Prigge, Zhiyu Li, Cassandra L. Woodard, Karine G. Le Roch, Christian Doerig, and Norman C. Waters
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Cyclin-Dependent Kinase Inhibitor p21 ,Cyclin D ,Plasmodium falciparum ,Cyclin A ,Protozoan Proteins ,Biophysics ,Protein Serine-Threonine Kinases ,Biology ,Binding, Competitive ,Biochemistry ,Cyclin-dependent kinase ,Cyclins ,Animals ,Humans ,Molecular Biology ,Cyclin-Dependent Kinase Inhibitor p16 ,Cyclin binding ,Cyclin-dependent kinase 1 ,Dose-Response Relationship, Drug ,Cyclin-dependent kinase 2 ,Cell Biology ,Cyclin-Dependent Kinases ,Recombinant Proteins ,Cell biology ,enzymes and coenzymes (carbohydrates) ,embryonic structures ,biology.protein ,Cyclin-dependent kinase complex ,Mitogen-Activated Protein Kinases ,biological phenomena, cell phenomena, and immunity ,Cyclin-Dependent Kinase-Activating Kinase ,Cyclin A2 - Abstract
The regulatory mechanisms of most cyclin dependent protein kinases (CDKs) are well understood and are highly conserved in eukaryotes. CDKs from the malaria parasite, Plasmodium falciparum, appear to be regulated in a similar manner with regard to cyclin binding and phosphorylation. In order to further understand their regulatory mechanisms, we examined two classes of cyclin dependent kinase inhibitors (CDIs) to inhibit a panel of plasmodial CDKs. We find that Pfmrk and PfPK5 are inhibited by heterologous p21(CIP1) with varying degrees of inhibition. In contrast, PfPK6, a kinase with sequence features characteristic of both a CDK and MAP kinase, is unaffected by this CDI. Furthermore, the CDK4/6 specific CDI, p16(INK4), fails to inhibit these plasmodial CDKs. Taken together, these results suggest that plasmodial CDKs may be regulated by the binding of inhibitory proteins in vivo.
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- 2001
11. Activation of a Plasmodium falciparum cdc2-related Kinase by Heterologous p25 and Cyclin H
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Norman C. Waters, Claude Sestier, Christian Doerig, Debopam Chakrabarti, Laurent Meijer, Barbara Kappes, Dominique Dorin, and Karine G. Le Roch
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Cyclin H ,Cyclin-dependent kinase 1 ,biology ,Kinase ,Plasmodium falciparum ,Cell Biology ,biology.organism_classification ,Biochemistry ,Cell biology ,Cyclin-dependent kinase ,Cyclin-dependent kinase complex ,biology.protein ,Molecular Biology ,Screening procedures ,CDC2 Protein Kinase - Abstract
Several Plasmodium falciparum genes encoding cdc2-related protein kinases have been identified, but the modalities of their regulation remains largely unexplored. In the present study, we investigated the regulation in vitro of PfPK5, a putative homologue of Cdk1 (cdc2) in P. falciparum. We show that (i) PfPK5 is efficiently activated by heterologous (human) cyclin H and p25, a cyclin-like molecule that specifically activates human Cdk5; (ii) the activated enzyme can be inhibited by chemical Cdk inhibitors; (iii) Pfmrk, a putative P. falciparum homologue of the Cdk-activating kinase, does neither activate nor phosphorylate PfPK5; and (iv) PfPK5 is able to autophosphorylate in the presence of a cyclin. Taken together, these results suggest that the regulation of Plasmodium Cdks may differ in important aspects from that of their human counterparts. Furthermore, we cloned an open reading frame encoding a novel P. falciparum protein possessing maximal homology to cyclin H from various organisms, and we show that this protein, called Pfcyc-1, is able to activate recombinant PfPK5 in vitro with an efficiency similar to that of human cyclin H and p25. This work opens the way to the development of screening procedures aimed at identifying compounds that specifically target the parasite Cdks.
- Published
- 2000
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