Structurally diverse mitochondrial branched chain aminotransferase (BCATm) leads with varying binding modes identified by fragment screening

Inhibitors of mitochondrial branched chain aminotransferase (BCATm), identified using fragment screening, are described. This was carried out using a combination of STD-NMR, thermal melt (Tm), and biochemical assays to identify compounds that bound to BCATm, which were subsequently progressed to X-ray crystallography, where a number of exemplars showed significant diversity in their binding modes. The hits identified were supplemented by searching and screening of additional analogues, which enabled the gathering of further X-ray data where the original hits had not produced liganded structures. The fragment hits were optimized using structure-based design, with some transfer of information between series, which enabled the identification of ligand efficient lead molecules with micromolar levels of inhibition, cellular activity, and good solubility

Development of a Series of Kynurenine 3-Monooxygenase Inhibitors Leading to a Clinical Candidate for the Treatment of Acute Pancreatitis

Recently, we reported a novel role for KMO in the pathogenesis of acute pancreatitis (AP). A number of inhibitors of kynurenine 3-monooxygenase (KMO) have previously been described as potential treatments for neurodegenerative conditions and particularly for Huntington’s disease. However, the inhibitors reported to date have insufficient aqueous solubility relative to their cellular potency to be compatible with the intravenous (iv) dosing route required in AP. We have identified and optimized a novel series of high affinity KMO inhibitors with favorable physicochemical properties. The leading example is exquisitely selective, has low clearance in two species, prevents lung and kidney damage in a rat model of acute pancreatitis, and is progressing into preclinical development

Kynurenine–3–monooxygenase inhibition prevents multiple organ failure in rodent models of acute pancreatitis

Acute pancreatitis (AP) is a common and devastating inflammatory condition of the pancreas that is considered to be a paradigm of sterile inflammation leading to systemic multiple organ dysfunction syndrome (MODS) and death1,2 Acute mortality from AP-MODS exceeds 20%3 and for those who survive the initial episode, their lifespan is typically shorter than the general population4. There are no specific therapies available that protect individuals against AP-MODS. Here, we show that kynurenine-3-monooxygenase (KMO), a key enzyme of tryptophan metabolism5, is central to the pathogenesis of AP-MODS. We created a mouse strain deficient for Kmo with a robust biochemical phenotype that protected against extrapancreatic tissue injury to lung, kidney and liver in experimental AP-MODS. A medicinal chemistry strategy based on modifications of the kynurenine substrate led to the discovery of GSK180 as a potent and specific inhibitor of KMO. The binding mode of the inhibitor in the active site was confirmed by X-ray co-crystallography at 3.2 Å resolution. Treatment with GSK180 resulted in rapid changes in levels of kynurenine pathway metabolites in vivo and afforded therapeutic protection against AP-MODS in a rat model of AP. Our findings establish KMO inhibition as a novel therapeutic strategy in the treatment of AP-MODS and open up a new area for drug discovery in critical illness

Nouvelles études de contaminations expérimentales d'espèces marines par le césium 137, le ruthénium 106 et le cérium 144

Des contaminations expérimentales d’espèces marines par des produits de fission ont été réalisées au Laboratoire de Radioécologie marine, C.E.A., Département de la Protection Sanitaire. Ces recherches destinées à apporter une contribution aux données permettant de situer les niveaux maximaux admissibles des rejets radioactifs en mer reposent sur la notion de « facteur de concentration » exprimant la capacité plus ou moins marquée des organismes à concentrer les radioéléments de provenances diverses présents dans le milieu marin. Les contaminations en aquariums, effectuées avec trois produits de fission : Césium 137, Ruthénium 106 et Cérium 144 ont surtout porté sur des espèces d’algues et d’invertébrés communs dans la région du nord-ouest du Cotentin. Elles ont permis de déterminer un certain nombre de facteurs de concentration qui ont été comparés aux résultats expérimentaux obtenus dans d’autres laboratoires et aux valeurs provenant de mesures faites dans le milieu naturel soumis à l’influence de rejets radioactifs

Contaminations de crevettes roses (leander serratus pen.) au moyen du cæsium 137 par voie alimentaire

Des contaminations expérimentales de crevettes roses ont été réalisées par ingestion de moules contaminées par le cæsium 137. Une brusque augmentation de la contamination est constatée après chaque repas, suivie d’une décontamination partielle. La contamination résiduelle est évaluée à 15 % environ de l’activité de la nourriture et une comparaison établie entre l’importance de la contamination due à l’ingestion et celle intervenant à partir du milieu ambiant montre la prépondérance de cette dernière

Real-time measurements of δ13C, CO2 concentration, and CO2/SO2 in volcanic plume gases at Mount Etna, Italy, over 5 consecutive days

We present new real-time measurements of the CO2 concentration and δ13C made from July 16 to 20, 2014 in diluted gases of the active plume emitted by the Central Craters at Mount Etna volcano, Italy. This innovative study involved measuring 13C in plume gases at a very high frequency over 5 days of measurements. The carbon-isotope composition calculated for volcanic CO2 ranged from –1.3‰ to +1.5‰, with uncertainties in the repeated single measurements (i.e., made over periods from 4 to 20 min) that were generally <0.7‰, and yet surprisingly varied by larger amounts over the 5-day study period. The range of calculated 13C values mostly overlaps with that indicated for the plume of the Central Craters obtained by discrete sampling and using the isotope-ratio mass spectrometry technique (–2.5‰ < 13C < –0.5‰). However, we propose that during particular conditions of volcanic activity, the carbon-isotope composition of CO2 degassed from magma can reach values (up to +1.5‰) that are higher than those reported previously. During this campaign we also made simultaneous measurements of the CO2 and SO2 concentrations using the MultiGAS technique. The volcanic 13C and CO2/SO2 ratios exhibited similar trends over the 5 days of measurements, with the ratios of both tracers peaking on July 16, possibly as a result of the early degassing of CO2 while an eruption was ongoing at Mount Etna. The observed variations and the highest 13C values measured at Mount Etna during this campaign lead to new questions about the variability of this geochemical tracer. The comparisons with the CO2/SO2 ratio also confirm that monitoring 13C in plume gases in real time, coupled to other geochemical tracers, is important for elucidating the magma dynamics at depth.Published182-1911V. Storia e struttura dei sistemi vulcanici2V. Dinamiche di unrest e scenari pre-eruttiviJCR Journalrestricte