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1.
Adele Boccuto Filippo Dragoni Francesca Picarazzi Alessia Lai Carla Della Ventura Carla Veo Federica Giammarino Francesco Saladini Gianguglielmo Zehender Maurizio Zazzi Mattia Mori Ilaria Vicenti 《International journal of molecular sciences》2021,22(5)
The nucleotide analog sofosbuvir, licensed for the treatment of hepatitis C, recently revealed activity against the Zika virus (ZIKV) in vitro and in animal models. However, the ZIKV genetic barrier to sofosbuvir has not yet been characterized. In this study, in vitro selection experiments were performed in infected human hepatoma cell lines. Increasing drug pressure significantly delayed viral breakthrough (p = 0.029). A double mutant in the NS5 gene (V360L/V607I) emerged in 3 independent experiments at 40–80 µM sofosbuvir resulting in a 3.9 ± 0.9-fold half- maximal inhibitory concentration (IC50) shift with respect to the wild type (WT) virus. A triple mutant (C269Y/V360L/V607I), detected in one experiment at 80 µM, conferred a 6.8-fold IC50 shift with respect to the WT. Molecular dynamics simulations confirmed that the double mutant V360L/V607I impacts the binding mode of sofosbuvir, supporting its role in sofosbuvir resistance. Due to the distance from the catalytic site and to the lack of reliable structural data, the contribution of C269Y was not investigated in silico. By a combination of sequence analysis, phenotypic susceptibility testing, and molecular modeling, we characterized a double ZIKV NS5 mutant with decreased sofosbuvir susceptibility. These data add important information to the profile of sofosbuvir as a possible lead for anti-ZIKV drug development. 相似文献
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Dr. Hui Qiu Richard Caldwell Dr. Lesley Liu-Bujalski Dr. Andreas Goutopoulos Reinaldo Jones Justin Potnick Dr. Brian Sherer Dr. Andrew Bender Dr. Roland Grenningloh Dr. Daigen Xu Dr. Anna Gardberg Dr. Igor Mochalkin Dr. Theresa Johnson Dr. Ariele Viacava Follis Jared Head Dr. Federica Morandi 《ChemMedChem》2019,14(2):217-223
Bruton's tyrosine kinase (Btk) is an attractive target for the treatment of a wide array of B-cell malignancies and autoimmune diseases. Small-molecule covalent irreversible Btk inhibitors targeting Cys481 have been developed for the treatment of such diseases. In clinical trials, probe molecules are required in occupancy studies to measure the level of engagement of the protein by these covalent irreversible inhibitors. The result of this pharmacodynamic (PD) activity provides guidance for appropriate dosage selection to optimize inhibition of the drug target and correlation of target inhibition with disease treatment efficacy. This information is crucial for successful evaluation of drug candidates in clinical trials. Based on the pyridine carboxamide scaffold of a novel solvent-accessible pocket (SAP) series of covalent irreversible Btk inhibitors, we successfully developed a potent and selective affinity-based biotinylated probe 12 (2-[(4-{4-[5-(1-{5-[(3aS,4S,6aR)-2-oxo-hexahydro-1H-thieno[3,4-d]imidazol-4-yl]pentanamido}-3,6,9,12-tetraoxapentadecan-15-amido)pentanoyl]piperazine-1-carbonyl}phenyl)amino]-6-[1-(prop-2-enoyl)piperidin-4-yl]pyridine-3-carboxamide). Compound 12 has been used in Btk occupancy assays for preclinical studies to determine the therapeutic efficacy of Btk inhibition in two mouse lupus models driven by TLR7 activation and type I interferon. 相似文献
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北京火车站抗震鉴定与加固技术 总被引:5,自引:3,他引:2
北京火车站抗震加固与改造设计项目组 《工程抗震与加固改造》2003,(1):25-29
北京火车站是首都重要的标志性建筑之一 ,195 9年建成 ,当时按 7度设防考虑 ,存在着许多不符合抗震要求的问题 ,一些设施也明显不能满足现代使用功能要求。北京火车站抗震加固与改造设计项目组 ,运用多种先进的加固手段 ,在保持原建筑外貌不变的前提下 ,实现了抗震能力和改善使用功能的协调 ,取得了大型公共建筑加固改造的新经验 相似文献
6.
对无缝钢管生产所用的内壁除鳞材料———除氧化物剂中各个组分的性质和作用进行了阐述,提出了除氧化物剂的除氧机理。 相似文献
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A FISH technique for simultaneous detection of fluorescent R-band and in situ hybridization signals]
BACKGROUND: Because of serious adverse effects of centrally acting antitussive agents, is necessary to find new drugs with cough-suppressing activity. Medicinal herbs are a potential source of polysaccharides with high antitussive efficiency and on the other with minimal side effects. AIM: The study was to assess the antitussive action of mixture of a polysaccharides (RL) and polysaccharide-xylan (XY), both isolated from above-ground parts of Rudbeckie fulgida var. sullivantii. The observed activity was compared to those of narcotic and nonnarcotic antitussive substances used in clinical practice. METHODS: Cough was evoked by mechanical irritation of the airways in nonanaesthetized cats with chronic tracheal cannuly. The plant substances were administered perorally in the dose of 50 mg per kg body weight. RESULTS: Results indicate, that administration of RL induced a suppression of the followed cough parameters from both areas of airways (total fall in cough parameters by 46.6%). Administration of xylan induced the fall in the followed cough parameters with more significant influence on the laryngopharyngeal area of the airways (total fall in cough parameters 48.2%). CONCLUSION: Administration of RL and xylan did not achieve the effect of codeine, but had a more intensive antitussive effect than the peripherally acting droprozine and prenoxdiazine. (Fig. 3, Ref. 11.) 相似文献
8.
Davide Barbagallo Angela Caponnetto Cristina Barbagallo Rosalia Battaglia Federica Mirabella Duilia Brex Michele Stella Giuseppe Broggi Roberto Altieri Francesco Certo Rosario Caltabiano Giuseppe Maria Vincenzo Barbagallo Carmelina Daniela Anfuso Gabriella Lupo Marco Ragusa Cinzia Di Pietro Thomas Birkballe Hansen Michele Purrello 《International journal of molecular sciences》2021,22(4)
Circular RNAs (circRNAs) are a large class of RNAs with regulatory functions within cells. We recently showed that circSMARCA5 is a tumor suppressor in glioblastoma multiforme (GBM) and acts as a decoy for Serine and Arginine Rich Splicing Factor 1 (SRSF1) through six predicted binding sites (BSs). Here we characterized RNA motifs functionally involved in the interaction between circSMARCA5 and SRSF1. Three different circSMARCA5 molecules (Mut1, Mut2, Mut3), each mutated in two predicted SRSF1 BSs at once, were obtained through PCR-based replacement of wild-type (WT) BS sequences and cloned in three independent pcDNA3 vectors. Mut1 significantly decreased its capability to interact with SRSF1 as compared to WT, based on the RNA immunoprecipitation assay. In silico analysis through the “Find Individual Motif Occurrences” (FIMO) algorithm showed GAUGAA as an experimentally validated SRSF1 binding motif significantly overrepresented within both predicted SRSF1 BSs mutated in Mut1 (q-value = 0.0011). U87MG and CAS-1, transfected with Mut1, significantly increased their migration with respect to controls transfected with WT, as revealed by the cell exclusion zone assay. Immortalized human brain microvascular endothelial cells (IM-HBMEC) exposed to conditioned medium (CM) harvested from U87MG and CAS-1 transfected with Mut1 significantly sprouted more than those treated with CM harvested from U87MG and CAS-1 transfected with WT, as shown by the tube formation assay. qRT-PCR showed that the intracellular pro- to anti-angiogenic Vascular Endothelial Growth Factor A (VEGFA) mRNA isoform ratio and the amount of total VEGFA mRNA secreted in CM significantly increased in Mut1-transfected CAS-1 as compared to controls transfected with WT. Our data suggest that GAUGAA is the RNA motif responsible for the interaction between circSMARCA5 and SRSF1 as well as for the circSMARCA5-mediated control of GBM cell migration and angiogenic potential. 相似文献
9.
液压系统设计与试验的虚拟样机技术 总被引:4,自引:0,他引:4
本文在介绍了虚拟样机技术的基础上,分析和阐述了开发具有虚拟样机功能的液压系统设计与试验软件的模型。 相似文献
10.
竹/玻璃钢复合建筑材料是一种新型三维复合材料.本文对其进行了结构设计的研究,并通过大量试验对其力学性能进行了分析,结果证明竹/玻璃钢复合建筑材料确实是一种重量轻、性能好、工艺简单、价格便宜的材料,具有广阔的应用前景. 相似文献