49 research outputs found

    Inhibition of D-Ala:D-Ala ligase through a phosphorylated form of the antibiotic D-cycloserine

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    D-cycloserine is an antibiotic which targets sequential bacterial cell wall peptidoglycan biosynthesis enzymes: alanine racemase and D-alanine:D-alanine ligase. By a combination of structural, chemical and mechanistic studies here we show that the inhibition of D-alanine:D-alanine ligase by the antibiotic D-cycloserine proceeds via a distinct phosphorylated form of the drug. This mechanistic insight reveals a bimodal mechanism of action for a single antibiotic on different enzyme targets and has significance for the design of future inhibitor molecules based on this chemical structure

    Argentine valerians: Traditional use and potential to treat neurodegenerative diseases

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    Las raíces de valeriana son sedantes/ansiolíticas e inductoras del sueño. Desde hace más de 20años estudiamos sus extractos y flavonoides neuroactivos. La enfermedad de Alzheimer (EA)es producida por acumulación anormal de proteínas (amiloide-β, tau) y metales pesados, estrésoxidativo y alteración de neurotransmisores (acetilcolina). Aquí presentamos un estudio de 5valerianas argentinas: Valeriana carnosa Sm., V. clarionifolia Phil., V. macrorhiza DC, V. ferax(Griseb.) Höck y V. effusa Griseb. (V. officinalis L., referencia). Validamos propiedadestranquilizantes de sus extractos en ensayos agudos en ratones Swiss machos [Marcucci y col.,Heliyon 6, e05691, 2020]. Evaluamos in vitro la presencia de: ligandos para el receptorGABAA: todas presentaron; inhibidores de acetil y butircolinesterasa (AChE/BChE)(Ellman): todas poseen (AChE murina IC50: 1.1-12.1 mg/ml y BChE murina IC50: 0.0018-1.46mg/ml) y de agregación Aβ1-42 (tioflavina T): V. effusa 93% y V. clarionifolia 82% (0.1 mg/ml).Propiedades antioxidantes (DPPH y ABTS): se observó relación directa con contenido decompuestos fenólicos. Inhibidores de monoaminooxidasas (MAO) A y B (Amplex red): sóloV. carnosa inhibió hMAO A (IC50: 300 µg/ml); fue estudiada en ratones (un mes, 100mg/kg/día, en agua de bebida), presentando mejora de memoria espacial (Y-maze), disminuciónde actividad AChE en cerebros y efecto símil-antidepresivo (Tail suspension). Nuestrasvalerianas son prometedoras para tratar la EA.Fil: Marcucci, Carolina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Físico-Química Biológicas "Prof. Alejandro C. Paladini". Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Físico-Química Biológicas; ArgentinaFil: Rademacher, Marina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Físico-Química Biológicas "Prof. Alejandro C. Paladini". Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Físico-Química Biológicas; ArgentinaFil: Kamecki González, Fabiola Elizabeth. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Físico-Química Biológicas "Prof. Alejandro C. Paladini". Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Físico-Química Biológicas; ArgentinaFil: Pastore, Valentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Físico-Química Biológicas "Prof. Alejandro C. Paladini". Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Físico-Química Biológicas; ArgentinaFil: Bach, H.. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; ArgentinaFil: Knez, D.. Universidad de Ljubljana; EsloveniaFil: Gobec, S.. Universidad de Ljubljana; EsloveniaFil: Wagner, M.. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; ArgentinaFil: Ricco, R.. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; ArgentinaFil: Colettis, Natalia Claudia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Físico-Química Biológicas "Prof. Alejandro C. Paladini". Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Físico-Química Biológicas; ArgentinaFil: Marder, M.. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Físico-Química Biológicas "Prof. Alejandro C. Paladini". Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Físico-Química Biológicas; ArgentinaVII Jornadas Nacionales de Plantas Aromáticas Nativas y sus Aceites Esenciales y III Jornadas Nacionales de Plantas Medicinales NativasArgentinaUniversidad Nacional de CórdobaSociedad Argentina de Botánic

    New Noncovalent Inhibitors of Penicillin-Binding Proteins from Penicillin-Resistant Bacteria

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    BACKGROUND: Penicillin-binding proteins (PBPs) are well known and validated targets for antibacterial therapy. The most important clinically used inhibitors of PBPs beta-lactams inhibit transpeptidase activity of PBPs by forming a covalent penicilloyl-enzyme complex that blocks the normal transpeptidation reaction; this finally results in bacterial death. In some resistant bacteria the resistance is acquired by active-site distortion of PBPs, which lowers their acylation efficiency for beta-lactams. To address this problem we focused our attention to discovery of novel noncovalent inhibitors of PBPs. METHODOLOGY/PRINCIPAL FINDINGS: Our in-house bank of compounds was screened for inhibition of three PBPs from resistant bacteria: PBP2a from Methicillin-resistant Staphylococcus aureus (MRSA), PBP2x from Streptococcus pneumoniae strain 5204, and PBP5fm from Enterococcus faecium strain D63r. Initial hit inhibitor obtained by screening was then used as a starting point for computational similarity searching for structurally related compounds and several new noncovalent inhibitors were discovered. Two compounds had promising inhibitory activities of both PBP2a and PBP2x 5204, and good in-vitro antibacterial activities against a panel of Gram-positive bacterial strains. CONCLUSIONS: We found new noncovalent inhibitors of PBPs which represent important starting points for development of more potent inhibitors of PBPs that can target penicillin-resistant bacteria.Eur-Intafa

    Preparation of Recombinant Human Hydroxysteroid Dehydrogenases and Study of their Inhibitors

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    Androgens and estrogens increase the number of cell division and the opportunity for random genetic errors and are thus involved in carcinogenesis of hormone related cancers. [...

    Tryptamine-derived compounds as antibacterial agents.

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    publication date: 2011-05-26; filing date: 2010-09-1

    Structural features and functional activities of benzimidazoles as NOD2 antagonists

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    NOD1 and NOD2 are pattern recognition receptors that have important roles in innate immune responses. Although their overactivation has been linked to a number of diseases, NOD2 in particular remains a virtually unexploited target in this respect, with only one structural class of antagonist reported. To gain insight into the structure-activity relationships of NOD2 antagonists, a series of novel analogs was designed and synthesized, and then screened for antagonist activity versus NOD2, and counter-screened versus NOD1. Compounds 32 and 38 were identified as potent and moderately selective NOD2 antagonists, and 33 and 42 as dual NOD1/NOD2 antagonists, with balanced activities against both targets in the low micromolar range. These data enable in-depth exploration of their structure-activity relationships and provide deeper understanding of the structural features required for NOD2 antagonism

    Combined liquid chromatography - tandem mass spectrometry analysis of progesterone metabolites.

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    Progesterone has a number of important functions throughout the human body. While the roles of progesterone are well known, the possible actions and implications of progesterone metabolites in different tissues remain to be determined. There is a growing body of evidence that these metabolites are not inactive, but can have significant biological effects, as anesthetics, anxiolytics and anticonvulsants. Furthermore, they can facilitate synthesis of myelin components in the peripheral nervous system, have effects on human pregnancy and onset of labour, and have a neuroprotective role. For a better understanding of the functions of progesterone metabolites, improved analytical methods are essential. We have developed a combined liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for detection and quantification of progesterone and 16 progesterone metabolites that has femtomolar sensitivity and good reproducibility in a single chromatographic run. MS/MS analyses were performed in positive mode and under constant electrospray ionization conditions. To increase the sensitivity, all of the transitions were recorded using the Scheduled MRM algorithm. This LC-MS/MS method requires small sample volumes and minimal sample preparation, and there is no need for derivatization. Here, we show the application of this method for evaluation of progesterone metabolism in the HES endometrial cell line. In HES cells, the metabolism of progesterone proceeds mainly to (20S)-20-hydroxy-pregn-4-ene-3-one, (20S)-20-hydroxy-5α-pregnane-3-one and (20S)-5α-pregnane-3α,20-diol. The investigation of possible biological effects of these metabolites on the endometrium is currently undergoing
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