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78. Distinct regulation by lipopolysaccharides of the expression of interleukin-1β by murine macrophages and salivary glands.

Author

Seil, M, Ouaaliti, M El, Abdou Foumekoye, S, Pochet, S, and Dehaye, JP

Subjects
LIPOPOLYSACCHARIDES, GENE expression, INTERLEUKIN-1, MACROPHAGES, SALIVARY gland diseases, CYTOKINES, LABORATORY mice
Abstract

The regulation of interleukin (IL)-1 expression and secretion by salivary glands and macrophages in response to lipopolysaccharides (LPS) was compared. In wild-type mice, injection of LPS significantly decreased the volume of saliva stimulated by pilocarpine and increased its protein and amylase concentration. It did not modify the salivary concentration of IL-1β. The cytokine was expressed by submandibular acini and ducts. Macrophages also expressed IL-1β but at lower concentration than salivary glands. The pre-incubation of macrophages with LPS increased the phosphorylation of IκB and the expression of IL-1β. Adenosine triphosphate also promoted the secretion of the cytokine by these cells. These responses were absent in submandibular gland cells. These glands expressed CD14, TLR4 and MyD88. P2X7-KO mice secreted a lower volume of saliva which contained less proteins and amylase. In conclusion, IL-1β is constitutively expressed by submandibular glands and its secretion is not regulated by a P2X7 agonist. In these cells, LPS do not activate the nuclear factor-κB–pro-IL-1β axis in spite of the expression of the proteins involved in their recognition. [ABSTRACT FROM PUBLISHER]

Published
2012
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80. A New Family of Inhibitors of Mycobacterium Tuberculosis Thymidine Monophosphate Kinase.

Author

Gasse, C., Huteau, V., Douguet, D., Munier-Lehmann, H., and Pochet, S.

Subjects
THYMIDINE, MYCOBACTERIUM tuberculosis, TUBERCULOSIS treatment, ALGORITHMS, LIGANDS (Biochemistry)
Abstract

The article examines thymidine monophosphates kinase of Mycobacterium tuberculosis (TMPKmt) as a potential target for developing new anti-tuberculosis agent. The researchers applied new fragment-based algorithm called LEA3D to the dTMP binding site of TMPKmt with the aim of generating new ligand families. They explore the inhibitory potency (ki) on recombinant TMPKmt.

Published
2007
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83. Role of sodium in mitochondrial membrane depolarization induced by P2X7 receptor activation in submandibular glands

Author

Garcia-Marcos, M., Fontanils, U., Aguirre, A., Pochet, S., Dehaye, J.P., and Marino, A.

Subjects
CELL membranes, APOPTOSIS, CELL death, ORGANIC compounds
Abstract

Abstract: The effect of ATP on mitochondrial membrane depolarization in rat submandibular glands was investigated. Exposure of the cell suspension to high concentrations of ATP induced a sustained depolarization of mitochondrial membrane. This effect was blocked in the presence of magnesium and reproduced by low concentrations of 2′,3′-O-(4-benzoylbenzoyl)adenosine 5′-triphosphate (BzATP), suggesting the implication of the P2X7 purinergic receptor. This point was confirmed by comparison of the response to ATP by wild-type and P2X7 knock-out (P2X7R−/−) mice. Mitochondria took up calcium after ATP stimulation but the depolarization of the mitochondrial membrane by ATP was not affected by the removal of calcium from the extracellular medium. It was nearly fully suppressed in the absence of sodium and partially blocked by the mitochondrial Na/Ca exchanger inhibitor 7-chloro-5-(2-chlorophenyl)-1,5-dihydro-4,1-benzothiazepin-2(3H)-one (CGP-37157). Both ATP and monensin increased the uptake of extracellular sodium (as shown by the depolarization of the plasma membrane) but the sodium ionophore did not affect the mitochondrial membrane potential. It is concluded that the activation of P2X7 receptors depolarizes the mitochondrial membrane. The uptake of extracellular sodium is necessary but not sufficient to induce this response. [Copyright &y& Elsevier]

Published
2005
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84. Design of Mycobacterium tuberculosis Thymidine Monophosphate Kinase Inhibitors.

Author

Munier-Lehmann, H., Pochet, S., Dugue, L., Dutruel, O., Labesse, G., and Douget, D.

Subjects
*THYMIDINE, *TUBERCULOSIS, *CELL proliferation, *AZIDOTHYMIDINE
Abstract

Discusses the role of the thymidine monophosphate kinase (TMPK) in cell proliferation and in the activation of antiviral drug AZT. Details of the M. tuberculosis; Description of TMPK.

Published
2003
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87. LEA3D: A Computer-Aided Ligand Design for Structure-Based Drug Design

Author

Douguet, D., Munier-Lehmann, H., Labesse, G., and Pochet, S.

Abstract

We present an improved version of the program LEA developed to design organic molecules. Rational drug design involves finding solutions to large combinatorial problems for which an exhaustive search is impractical. Genetic algorithms provide a tool for the investigation of such problems. New software, called LEA3D, is now able to conceive organic molecules by combining 3D fragments. Fragments were extracted from both biological compounds and known drugs. A fitness function guides the search process in optimizing the molecules toward an optimal value of the properties. The fitness function is build up by combining several independent property evaluations, including the score provided by the FlexX docking program. One application in de novo drug design is described. The example makes use of the structure of Mycobacterium tuberculosis thymidine monophosphate kinase to generate analogues of one of its natural substrates. Among 22 tested compounds, 17 show inhibitory activity in the micromolar range.

Published
2005

88. 3‘-C-Branched-Chain-Substituted Nucleosides and Nucleotides as Potent Inhibitors of Mycobacterium tuberculosis Thymidine Monophosphate Kinase

Author

Vanheusden, V., Munier-Lehmann, H., Froeyen, M., Dugue, L., Heyerick, A., Keukeleire, D. De, Pochet, S., Busson, R., Herdewijn, P., and Calenbergh, S. Van

Abstract

Thymidine monophosphate kinase (TMPK) of Mycobacterium tuberculosis (TMPKmt) represents an attractive target for blocking the bacterial DNA synthesis. In an attempt to find high-affinity inhibitors of TMPKmt, a cavity in the enzyme at the 3‘-position was explored via the introduction of various substituents at the 3‘-position of the thymidine monophosphate (dTMP) scaffold. Various 3‘-C-branched chain substituted nucleotides in the 2‘-deoxyribo (3−6) and ribo series (7, 8) were synthesized from one key intermediate (23). 2‘-Deoxy analogues proved to be potent inhibitors of TMPKmt:  3‘-CH2NH2 (4), 3‘-CH2N3 (3), and 3‘-CH2F (5) nucleotides exhibit the highest affinities within this series, with Ki values of 10.5, 12, and 15 μM, respectively. These results show that TMPKmt tolerates the introduction of sterically demanding substituents at the 3‘-position. Ribo analogues experience a significant affinity decrease, which is probably due to steric hindrance of Tyr103 in close vicinity of the 2‘-position. Although the 5‘-O-phosphorylated compounds have somewhat higher affinities for the enzyme, the parent nucleosides generally exhibit affinities for TMPKmt in the same order of magnitude and display a superior selectivity profile versus human TMPK. This series of inhibitors holds promise for the development of a new class of antituberculosis agents.

Published
2003

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