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51.
B. Narasimhulu Naidu Michael A. Walker Margaret E. Sorenson Yasutsugu Ueda John D. Matiskella Timothy P. Connolly Ira B. Dicker Zeyu Lin Sagarika Bollini Brian J. Terry Helen Higley Ming Zheng Dawn D. Parker Dedong Wu Stephen Adams Mark R. Krystal Nicholas A. Meanwell 《Bioorganic & medicinal chemistry letters》2018,28(12):2124-2130
BMS-707035 is an HIV-1 integrase strand transfer inhibitor (INSTI) discovered by systematic optimization of N-methylpyrimidinone carboxamides guided by structure-activity relationships (SARs) and the single crystal X-ray structure of compound 10. It was rationalized that the unexpectedly advantageous profiles of N-methylpyrimidinone carboxamides with a saturated C2-substitutent may be due, in part, to the geometric relationship between the C2-substituent and the pyrimidinone core. The single crystal X-ray structure of 10 provided support for this reasoning and guided the design of a spirocyclic series 12 which led to discovery of the morpholino-fused pyrimidinone series 13. Several carboxamides derived from this bicyclic scaffold displayed improved antiviral activity and pharmacokinetic profiles when compared with corresponding spirocyclic analogs. Based on the excellent antiviral activity, preclinical profiles and acceptable in vitro and in vivo toxicity profiles, 13a (BMS-707035) was selected for advancement into phase I clinical trials. 相似文献
52.
Single step recombinant human growth hormone (rhGH) purification from milk by peptide affinity chromatography
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Soledad L. Saavedra María C. Martínez Ceron Silvana L. Giudicessi Guillermina Forno María Belén Bosco Mariela M. Marani Rosa Erra‐Balsells Fernando Albericio Osvaldo Cascone Silvia A. Camperi 《Biotechnology progress》2018,34(4):999-1005
Recombinant human growth hormone (rhGH) is used for the treatment of several pathologies, most of them related to growth. Although different expression systems can be used for its production, the milk from transgenic cows is one of the most interesting due to the high rhGH level achieved (5 g/L). We have designed and synthesized short peptides (9 or 10 amino acid long) using Fmoc chemistry and studied their ability to purify rhGH from milk once immobilized on an agarose support. Using spiked milk with the hormone as a sample, rhGH was purified with 88% yield and 92% purity in a single step with a fold purification of 4.5. © 2018 American Institute of Chemical Engineers Biotechnol. Prog., 34:999–1005, 2018 相似文献
53.
The Rate of Phaseolin Assembly Is Controlled by the Glucosylation State of Its N-Linked Oligosaccharide Chains 总被引:6,自引:2,他引:4
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Many of the proteins that are translocated into the endoplasmic reticulum are glycosylated with the addition of a 14-saccharide core unit (Glc3Man9GlcNAc2) to specific asparagine residues of the nascent polypeptide. Glucose residues are then removed by endoplasmic reticulum-located glucosidases, with diglucosylated and monoglucosylated intermediates being formed. In this study, we used a cell-free system constituted of wheat germ extract and bean microsomes to examine the role of glucose trimming in the structural maturation of phaseolin, a trimeric glycoprotein that accumulates in the protein storage vacuoles of bean seeds. Removal of glucose residues from the N-linked chains of phaseolin was blocked by the glucosidase inhibitors castanospermine and N-methyldeoxynojirimycin. If glucose trimming was not allowed to occur, the assembly of phaseolin was accelerated. Conversely, polypeptides bearing partially trimmed glycans were unable to form trimers. The effect of castanospermine on the rate of assembly was much more pronounced for phaseolin polypeptides that have two glycans but was also evident when a single glycan chain was present, indicating that glycan clustering can modulate the effect of glucose trimming on the rate of trimer formation. Therefore, the position of glycan chains and their accessibility to the action of glucosidases can be fundamental elements in the control of the structural maturation of plant glycoproteins. 相似文献
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Daviel Gómez Lázaro Hernández Bárbara Valle Julia Martínez Mariela Cid Maritza Escalona Martha Hernández Gerrit T. S. Beemster Christoph C. Tebbe Lourdes Yabor José Carlos Lorenzo 《Acta Physiologiae Plantarum》2017,39(12):277
Effects of salinity (NaCl) and the carbon source mannitol (0–200 mM) on micropropagation of pineapple cv. MD2 were analyzed in temporary immersion bioreactors (TIBs). Shoot multiplication rate, shoot cluster fresh weight and levels of aldehydes, chlorophylls, carotenoids and phenolics were determined in the plant material. The content of soluble phenolics in the culture medium was also evaluated. NaCl or mannitol above concentrations of 50 mM decreased pineapple shoot multiplication and fresh weight significantly. Two hundred mM NaCl decreased multiplication rate by 71.5% and cluster fresh weight by 40.0%. NaCl increased 2.4 times the levels of other aldehydes; 1.4 times the soluble phenolics in shoots; and 1.4 times the phenolics excreted to the culture medium. On the other hand, mannitol decreased the multiplication rate and cluster fresh weight by about 60%. Mannitol increased the contents of chlorophyll b 1.4 times and soluble phenolics 2.1 times. Results indicated that pineapple cv. MD2 is more sensitive to NaCl than to mannitol. Multiplication rates indicate that a 50% reduction was obtained with 37.4 mM NaCl and 66.5 mM mannitol. These concentrations can be used to stress shoots during micropropagation in TIBs and screen for/detect somaclonal variants with an increased salinity or drought tolerance. 相似文献
59.
Letek M Ocampo-Sosa AA Sanders M Fogarty U Buckley T Leadon DP González P Scortti M Meijer WG Parkhill J Bentley S Vázquez-Boland JA 《Journal of bacteriology》2008,190(17):5797-5805
The pathogenic actinomycete Rhodococcus equi harbors different types of virulence plasmids associated with specific nonhuman hosts. We determined the complete DNA sequence of a vapB(+) plasmid, typically associated with pig isolates, and compared it with that of the horse-specific vapA(+) plasmid type. pVAPB1593, a circular 79,251-bp element, had the same housekeeping backbone as the vapA(+) plasmid but differed over an approximately 22-kb region. This variable region encompassed the vap pathogenicity island (PAI), was clearly subject to selective pressures different from those affecting the backbone, and showed major genetic rearrangements involving the vap genes. The pVAPB1593 PAI harbored five different vap genes (vapB and vapJ to -M, with vapK present in two copies), which encoded products differing by 24 to 84% in amino acid sequence from the six full-length vapA(+) plasmid-encoded Vap proteins, consistent with a role for the specific vap gene complement in R. equi host tropism. Sequence analyses, including interpolated variable-order motifs for detection of alien DNA and reconstruction of Vap family phylogenetic relationships, suggested that the vap PAI was acquired by an ancestor plasmid via lateral gene transfer, subsequently evolving by vap gene duplication and sequence diversification to give different (host-adapted) plasmids. The R. equi virulence plasmids belong to a new family of actinobacterial circular replicons characterized by an ancient conjugative backbone and a horizontally acquired niche-adaptive plasticity region. 相似文献
60.
María A. Lopez Verrilli Carlos J. Pirola† Mariano M. Pascual‡ Fernando P. Dominici Daniel Turyn Mariela M. Gironacci 《Journal of neurochemistry》2009,109(2):326-335
Hypothalamic norepinephrine (NE) release regulates arterial pressure by altering sympathetic nervous system activity. Because angiotensin (Ang) (1–7) decreases hypothalamic NE release and this effect may be correlated with a diminished NE synthesis, we hypothesize that Ang-(1–7) down-regulates tyrosine hydroxylase (TH), the rate-limiting enzyme in catecholamines biosynthesis. We investigated the effect of Ang-(1–7) on centrally TH activity and expression. TH activity was evaluated by the release of tritiated water from 3 H- l -tyrosine. TH expression and phosphorylation were determined by western blot. Hypothalami from normotensive or spontaneously hypertensive rats pre-incubated with Ang-(1–7) showed a significant decrease in TH specific activity. Ang-(1–7) caused a decrease in TH phosphorylation at Ser19 and Ser40 residues. The heptapeptide induced a decrease in TH expression that was blocked by an AT2 receptor antagonist and not by an AT1 or Mas receptor antagonist, suggesting the involvement of AT2 receptors. The proteasome inhibitor MG132 blocked the Ang-(1–7)-mediated TH reduction. In addition, Ang-(1–7) increased the amount of TH–ubiquitin complexes, indicating that the Ang-(1–7)-mediated TH degradation involves ubiquitin conjugation prior to proteasome degradation. We conclude that Ang-(1–7) down-regulates TH activity and expression centrally leading to a decrease in the central NE system activity. 相似文献