53 research outputs found
Metabolic aspects of glycosomes in trypanosomatidae - new data and views.
No full textThe energy metabolism of Trypanosomatidae has been the subject of many reviews during the past decade. In recent years, however, new data have led to a more complete picture of trypanosomatid metabolism and a reappraisal of the role of some characteristic organelles in the energy supply of these parasites. For years, the glycosome was thought to be a peroxisome-like organelle that had evolved to allow the parasites to carry out glycolysis at a high rate using a relatively small amount of enzyme. However, the results of recent studies of trypanosomatid glycolysis and the detection of various other pathways and enzymes in the organelle necessitate a modification of this view. Here, Paul Michels, Véronique Hannaert and Frédéric Bringaud review the new data and discuss the possible implications for our view on the role of the glycosome
Designing a Context-aware Decentralized Marketplace for Sensor Data
No full textIn the past years there has been increasing awareness about the benefits of collecting and using more sensor data for businesses. This has led firms to look for data outside of their boundaries and use some data commercialization mechanisms such as data brokers, and open or privately-owned data marketplace. However, these exchanges solutions are controlled by companies which have a commercial interest that differs from users, leading to lack of transparency and lack of protection of data, loss of data ownership by the provider and no guarantee of fair pricing. These centralized data exchanges call into question the willingness of both data providers and data users to share data. As an alternative, blockchain technology can be used to reduce the control and interference of any firm, leading to a more peer-to-peer and transparent data marketplace. To improve coordination between stakeholders and to enhance a more automated marketplace, the system should be context-aware. The main contribution of this thesis is a proposition of blockchain-based components integrated within a context-aware decentralized data marketplace. Other parts of the system are highlighted, as they need to be subject to more research in order to achieve a fully functional and complete system. Finally, guidelines are suggested for generalization to other types of data and ecosystems.Management of Technology (MoT
Virtual screening identification of nonfolate compounds, including a CNS drug, as antiparasitic agents inhibiting pteridine reductase
No full textFolate analogue inhibitors of Leishmania major pteridine reductase (PTR1) are potential antiparasitic drug candidates for combined therapy with dihydrofolate reductase (DHFR) inhibitors. To identify new molecules with specificity for PTR1, we carried out a virtual screening of the Available Chemicals Directory (ACD) database to select compounds that could interact with L. major PTR1 but not with human DHFR. Through two rounds of drug discovery, we successfully identified eighteen drug-like molecules with low micromolar affinities and high in vitro specificity profiles. Their efficacy against Leishmania species was studied in cultured cells of the promastigote stage, using the compounds both alone and in combination with 1 (pyrimethamine; 5-(4-chlorophenyl)-6-ethylpyrimidine-2,4-diamine). Six compounds showed efficacy only in combination. In toxicity tests against human fibroblasts, several compounds showed low toxicity. One compound, 5c (riluzole; 6-(trifluoromethoxy)- 1,3-benzothiazol-2-ylamine), a known drug approved for CNS pathologies, was active in combination and is suitable for early preclinical evaluation of its potential for label extension as a PTR1 inhibitor and antiparasitic drug candidate. © 2010 American Chemical Society
Structure-based selectivity optimization of piperidine-pteridine derivatives as potent leishmania pteridine reductase inhibitors.
No full textThe upregulation of pteridine reductase (PTR1) is a
major contributor to antifolate drug resistance in Leishmania spp., as it
provides a salvage pathway that bypasses dihydrofolate reductase
(DHFR) inhibition. The structure-based optimization of the PTR1
inhibitor methyl-1-[4-(2,4-diaminopteridin-6-ylmethylamino)benzoyl]-
piperidine-4-carboxylate (1) led to the synthesis of a focused compound
library which showed significantly improved selectivity for the parasite’s
folate-dependent enzyme. When used in combination with pyrimethamine,
a DHFR inhibitor, a synergistic effect was observed for
compound 5b. This work represents a step forward in the identification
of effective antileishmania agents
Structure-based selectivity optimization of piperidine-pteridine derivatives as potent Leishmania pteridine reductase inhibitors.
No full textThe upregulation of pteridine reductase (PTR1) is a major contributor to antifolate drug resistance in Leishmania spp., as it provides a salvage pathway that bypasses dihydrofolate reductase (DHFR) inhibition. The structure-based optimization of the PTR1 inhibitor methyl-1-[4-(2,4-diaminopteridin-6-ylmethylamino)benzoyl]piperidine-4-carboxylate (1) led to the synthesis of a focused compound library which showed significantly improved selectivity for the parasite's folate-dependent enzyme. When used in combination with pyrimethamine, a DHFR inhibitor, a synergistic effect was observed for compound 5b. This work represents a step forward in the identification of effective antileishmania agents
Dynamic modelling under uncertainty: the case of Trypanosoma brucei energy metabolism
No full textKinetic models of metabolism require detailed knowledge of kinetic parameters. However, due to measurement errors or lack of data this knowledge is often uncertain. The model of glycolysis in the parasitic protozoan Trypanosoma brucei is a particularly well analysed example of a quantitative metabolic model, but so far it has been studied with a fixed set of parameters only. Here we evaluate the effect of parameter uncertainty. In order to define probability distributions for each parameter, information about the experimental sources and confidence intervals for all parameters were collected. We created a wiki-based website dedicated to the detailed documentation of this information: the SilicoTryp wiki (http://silicotryp.ibls.gla.ac.uk/wiki/Glycolysis). Using information collected in the wiki, we then assigned probability distributions to all parameters of the model. This allowed us to sample sets of alternative models, accurately representing our degree of uncertainty. Some properties of the model, such as the repartition of the glycolytic flux between the glycerol and pyruvate producing branches, are robust to these uncertainties. However, our analysis also allowed us to identify fragilities of the model leading to the accumulation of 3-phosphoglycerate and/or pyruvate. The analysis of the control coefficients revealed the importance of taking into account the uncertainties about the parameters, as the ranking of the reactions can be greatly affected. This work will now form the basis for a comprehensive Bayesian analysis and extension of the model considering alternative topologies
Antiplasmodial and antitrypanosomal activity of Triclisia sacleuxii (Pierre) Diels.
No full textThe antiplasmodial and antitrypanosomal activities of Triclisia sacleuxii (Pierre) Diels were investigated on three Plasmodium falciparum strains [FcB1, 3D7 (chloroquine-sensitive) and W2 (chloroquine-resistant) strains] and on Trypanosoma brucei Tbsf 221. Roots, stems and leaves ethanolic extracts as well as crude tertiary and quaternary alkaloids fractions were considered. Whereas the ethanolic extracts and quaternary crude alkaloids fractions exhibited no significant activity, the roots and stems tertiary alkaloid fractions revealed interesting growth inhibition against the Plasmodium FcB1 and Trypanosoma Tbsf 221 strains. The IC(50) were 1.04 and 0.89 microg/ml for roots, 2.50 and 0.91 microg/ml for stems. The leaves tertiary alkaloids fraction also showed a promising antitrypanosomal activity (IC(50): 1.85 microg/ml). Phytochemical analysis of the roots tertiary alkaloids fraction yielded four major compounds, phaeanthine, N-methylapateline, 1,2-dehydroapateline and 1,2-dehydrotelobine, which were identified on the basis of their spectroscopic data. The four compounds displayed (in vitro) antitrypanosomal activity with IC(50) of 2.68, 1.19, 1.06 and 1.11 microM, respectively. They also demonstrated antiplasmodial activity on Plasmodium falciparum 3D7, with IC(50) of 1.72, 0.93, 1.39 and 12.4 microM respectively and on the chloroquine-resistant W2 with IC(50) of 0.35, 1.10, 1.63 and 1.52 microM.In VitroJournal ArticleResearch Support, Non-U.S. Gov'tinfo:eu-repo/semantics/publishe
Antitrypanosomal activity of polycarpol from Piptostigma preussi (Annonaceae).
No full textPolycarpol, sitosterol and sitosterol-3-O-beta-D-glucoside isolated for the first time from Piptostigma preussi (Annonaceae) occur regularly in some Annonaceae such as Piptostigma genus. Polycarpol exhibits interesting antitrypanosomal activity with an ED(50) value of 5.11 muM on Trypanosoma brucei cells. Moreover, it inhibits T. brucei glycolytic enzymes GAPDH and PFK with IC(50) values of 650 and 180 muM respectively
Antitrypanosomal alkaloids from Polyalthia suaveolens (Annonaceae): Their effects on three selected glycolytic enzymes of Trypanosoma brucei
No full textIn continuation of our study on medicinal plants of Cameroon, stem barks of Polyalthia suaveolens were phytochemically studied. This investigation yielded a new indolosesquiterpene alkaloid, named polysin (1) and four hitherto known alkaloids (2-5). Polysin (1) appeared as a competitive reversible inhibitor (K-i = 10 mu M) of phosphofructo kinase (PFK) of Trypanosoma brucei with respect to fructose-6-phosphate (K-i/K-M = 0.05) and could be used in the design of new trypanocidal drugs. The other isolated compounds (2-5) also exhibited interesting inhibitory effects on selected glycolytic enzymes (PFK, glyceraldehyde-3-phosphate dehydrogenase and aldolase). Crown Copyright (C) 2010 Published by Elsevier Ltd. All rights reserved
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