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排序方式: 共有198条查询结果,搜索用时 15 毫秒
151.
Zhang HW Zhou L Coats SJ McBrayer TR Tharnish PM Bondada L Detorio M Amichai SA Johns MD Whitaker T Schinazi RF 《Bioorganic & medicinal chemistry letters》2011,21(22):6788-6792
Based on the anti-hepatitis C activity of 2′-C-methyl-adenosine and 2′-C-methyl-guanosine, a series of new modified purine 2′-C-methyl nucleosides was prepared as potential anti-hepatitis C virus agents. Herein, we report the synthesis of both 6-modified and 2-modified purine 2′-C-methyl-nucleosides along with their anti-HCV replication activity and cytotoxicity in different cells. 相似文献
152.
Shi J Zhou L Zhang H McBrayer TR Detorio MA Johns M Bassit L Powdrill MH Whitaker T Coats SJ Götte M Schinazi RF 《Bioorganic & medicinal chemistry letters》2011,21(23):7094-7098
Thirty novel α- and β-d-2'-deoxy-2'-fluoro-2'-C-methyl-7-deazapurine nucleoside analogs were synthesized and evaluated for in vitro antiviral activity. Several α- and β-7-deazapurine nucleoside analogs exhibited modest anti-HCV activity and cytotoxicity. Four synthesized 7-deazapurine nucleoside phosphoramidate prodrugs (18-21) showed no anti-HCV activity, whereas the nucleoside triphosphates (22-24) demonstrated potent inhibitory effects against both wild-type and S282T mutant HCV polymerases. Cellular pharmacology studies in Huh-7 cells revealed that the 5'-triphosphates were not formed at significant levels from either the nucleoside or the phosphoramidate prodrugs, indicating that insufficient phosphorylation was responsible for the lack of anti-HCV activity. Evaluation of anti-HIV-1 activity revealed that an unusual α-form of 7-carbomethoxyvinyl substituted nucleoside (10) had good anti-HIV-1 activity (EC(50)=0.71±0.25 μM; EC(90)=9.5±3.3 μM) with no observed cytotoxicity up to 100 μM in four different cell lines. 相似文献
153.
154.
155.
Zhang H Zhou L Amblard F Shi J Bobeck DR Tao S McBrayer TR Tharnish PM Whitaker T Coats SJ Schinazi RF 《Bioorganic & medicinal chemistry letters》2012,22(14):4864-4868
Judicious modifications to the structure of the previously reported HCV NS5A inhibitor 1, resulted in more potent anti-HCV compounds with similar and in some cases improved toxicity profiles. The synthesis of 19 new NS5A inhibitors is reported along with their ability to block HCV replication in an HCV 1b replicon system. For the most potent compounds chemical stability, stability in liver microsomes and inhibition of relevant CYP450 enzymes is also presented. 相似文献
156.
Janet L. Ralbovsky Joseph G. Lisko Jeffrey M. Palmer John Mabus Kristen M. Chevalier Mark J. Schulz Alexey B. Dyatkin Tamara A. Miskowski Steven J. Coats Pamela Hornby Wei He 《Bioorganic & medicinal chemistry letters》2009,19(10):2661-2663
A series of guanidine triazinediones were identified as potent PK1 receptor antagonists. A compound in this series inhibited the PK1 invoked prosecretory response in rat ileum tissue. 相似文献
157.
Stephen R. Coats Jace W. Jones Christopher T. Do Pamela H. Braham Brian W. Bainbridge Thao T. To David R. Goodlett Robert K. Ernst Richard P. Darveau 《Cellular microbiology》2009,11(11):1587-1599
Signal transduction following binding of lipopolysaccharide (LPS) to Toll-like receptor 4 (TLR4) is an essential aspect of host innate immune responses to infection by Gram-negative pathogens. Here, we describe a novel molecular mechanism used by a prevalent human bacterial pathogen to evade and subvert the human innate immune system. We show that the oral pathogen, Porphyromonas gingivalis , uses endogenous lipid A 1- and 4'-phosphatase activities to modify its LPS, creating immunologically silent, non-phosphorylated lipid A. This unique lipid A provides a highly effective mechanism employed by this bacterium to evade TLR4 sensing and to resist killing by cationic antimicrobial peptides. In addition, lipid A 1-phosphatase activity is suppressed by haemin, an important nutrient in the oral cavity. Specifically, P. gingivalis grown in the presence of high haemin produces lipid A that acts as a potent TLR4 antagonist. These results suggest that haemin-dependent regulation of lipid A 1-dephosphorylation can shift P. gingivalis lipid A activity from TLR4 evasive to TLR4 suppressive, potentially altering critical interactions between this bacterium, the local microbial community and the host innate immune system. 相似文献
158.
Adenovirus-mediated transfer of the muscle glycogen phosphorylase gene into hepatocytes confers altered regulation of glycogen metabolism. 总被引:3,自引:0,他引:3
A M Gómez-Foix W S Coats S Baqué T Alam R D Gerard C B Newgard 《The Journal of biological chemistry》1992,267(35):25129-25134
The muscle isozyme of glycogen phosphorylase is potently activated by the allosteric ligand AMP, whereas the liver isozyme is not. In this study we have investigated the metabolic impact of expression of muscle phosphorylase in liver cells. To this end, we constructed a replication-defective, recombinant adenovirus containing the muscle glycogen phosphorylase cDNA (termed AdCMV-MGP) and used this system to infect hepatocytes in culture. AMP-activatable glycogen phosphorylase activity was increased 46-fold 6 days after infection of primary liver cells with AdCMV-MGP. Despite large increases in phosphorylase activity, glycogen levels were only slightly reduced in AdCMV-MGP-infected liver cells compared to uninfected cells or cells infected with wild-type adenovirus. The lack of correlation of phosphorylase activity and glycogen content suggests that the liver cell environment can inhibit the muscle phosphorylase isozyme. This inhibition can be overcome, however, by addition of carbonyl cyanide m-chlorophenylhydrazone (CCCP), which increases AMP levels by 30-fold and causes a much larger decrease in glycogen levels in AdCMV-MGP-infected cells than in uninfected or wild-type adenovirus-infected controls. CCCP treatment also caused a preferential decrease in glycogen content relative to glucagon treatment in AdCMV-MGP-infected hepatocytes (74% versus 11%, respectively), even though the two drugs caused equal increases in phosphorylase a activity. Introduction of muscle phosphorylase into hepatocytes therefore confers a capacity for glycogenolytic response to effectors that is not provided by the endogenous liver phosphorylase isozyme. The remarkable efficiency of adenovirus-mediated gene transfer into primary hepatocytes and the demonstration of altered regulation of glycogen metabolism as a consequence of expression of a non-cognate phosphorylase isozyme may have implications for gene therapy of glycogen storage diseases. 相似文献
159.
V. P. Marshall J. H. Coats L. Baczynskyj J. I. Cialdella W. F. Liggett J. E. McGee 《Journal of industrial microbiology & biotechnology》1990,6(4):295-297
Summary An enzyme that catalyzes 2-O-phosphorylation of oleandomycin and several other macrolide antibiotics has been purified approximately 47-fold from cell-free extracts ofStreptomyces coelicolor Müller, NRRL 3532 (UC 5240). The reaction product was verified as being oleandomycin-2-O-phosphate by mass spectrometry. As a result of purification, the enzyme was separated from two lincosaminide inactivating enzyme activities also present in the cell-free extract. 相似文献
160.