排序方式: 共有9条查询结果,搜索用时 15 毫秒
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Antony N. Shaw Rosanna Tedesco Ramesh Bambal Deping Chai Nestor O. Concha Michael G. Darcy Dashyant Dhanak Kevin J. Duffy Duke M. Fitch Adam Gates Victor K. Johnston Richard M. Keenan Juili Lin-Goerke Nannan Liu Robert T. Sarisky Kenneth J. Wiggall Michael N. Zimmerman 《Bioorganic & medicinal chemistry letters》2009,19(15):4350-4353
The synthesis and optimisation of HCV NS5B polymerase inhibitors with improved potency versus the existing compound 1 is described. Substitution in the benzothiadiazine portion of the molecule, furnishing improvement in potency in the high protein Replicon assay, is highlighted, culminating in the discovery of 12h, a highly potent oxyacetamide derivative. 相似文献
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Evans KA Chai D Graybill TL Burton G Sarisky RT Lin-Goerke J Johnston VK Rivero RA 《Bioorganic & medicinal chemistry letters》2006,16(8):2205-2208
An efficient, asymmetric solid-phase synthesis of benzothiadiazine-substituted tetramic acids is reported. Starting from commercially available chiral Fmoc-protected alpha-amino acids loaded onto Wang resin, Fmoc removal, reductive amination followed by amide bond formation, and base-catalyzed cyclization with simultaneous cleavage from the resin provided the desired products. Compounds described are potent inhibitors of the hepatitis C virus RNA-dependent RNA polymerase. 相似文献
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P Vissavajjhala J D Leszyk J Lin-Goerke A H Ross 《Archives of biochemistry and biophysics》1992,294(1):244-252
Using partial proteolytic cleavage, the nerve growth factor (NGF) binding site and the epitopes for two anti-NGF receptor (NGFR) monoclonal antibodies were localized on the recombinant extracellular domain (RED) of the NGFR. The RED was prepared in the baculovirus-insect cell system and was purified by immunoaffinity and ion-exchange chromatography. The four cysteine-rich repeat domains and some additional C-terminal sequences were resistant to proteolysis with papain or proteinase K. The Mr 32,000 papain-resistant fragment (P32) and the Mr 30,000 proteinase K-resistant fragment (K30) share the same N terminus as the intact RED and have C termini in the vicinity of residue 170. Even though P32 and K30 have the same N terminus and probably differ by only a small number of amino acids at the C terminus, P32, but not K30, binds 125I-NGF. As judged by Western blot analysis, two anti-NGFR antibodies (ME20.4 and NGFR5) bind to P32 but have a lesser affinity for K30. Since antibody ME20.4 inhibits NGF binding but antibody NGFR5 does not, these antibodies bind to distinct epitopes. However, these epitopes apparently are closely spaced since these antibodies compete with each other for binding to biotinylated RED. NGF, but not the control protein cytochrome c, protects RED from papain digestion. Therefore, the P32 C terminus is important for the expression of the NGF binding site and the antibody-defined epitopes, even though the NGF binding site and antibody-defined epitopes probably are not encoded by the P32 C terminus. These data suggest that complex interactions occur between different regions of the RED, and that optimum NGF binding requires the integrity of multiple RED domains, including a short sequence to the C terminus of residue 170. 相似文献
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Burton G Ku TW Carr TJ Kiesow T Sarisky RT Lin-Goerke J Hofmann GA Slater MJ Haigh D Dhanak D Johnson VK Parry NR Thommes P 《Bioorganic & medicinal chemistry letters》2007,17(7):1930-1933
The SAR development is described for a series of N-acyl pyrrolidine inhibitors of the Hepatitis C virus RNA-dependent RNA polymerase, NS5B, from tractable Delta21 enzyme inhibitors to an example with antiviral activity in a cellular assay (HCV replicon). 相似文献
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Gu B Gutshall LL Maley D Pruss CM Nguyen TT Silverman CL Lin-Goerke J Khandekar S Liu C Baker AE Casper DJ Sarisky RT 《Biochemical and biophysical research communications》2004,313(2):343-350
The nonstructural protein 5B (NS5B) of hepatitis C virus (HCV) encodes an RNA-dependent RNA polymerase (RdRp) which is essential for viral replication. NS5B expression in bacteria generated 20- to 50-fold lower yield and 100-fold less product per mol of enzyme for gentoype 1a RdRp than type 1b. Further, unlike type 1b RdRp, type 1a enzyme failed to exhibit cooperative properties in the assays described herein. Differences in thermal stability may partially account for the inability to efficiently oligomerize. Superose gel filtration analyses confirm differences between these RdRp preparations, although affinity for the column rather than size may account for the differences in migration. To further address this complexity, a panel of RdRp type 1a-type 1b chimeras were evaluated and implicate a role for the thumb subdomain of genotype 1b RdRp as critical for cooperative function. 相似文献
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Identification and biological characterization of heterocyclic inhibitors of the hepatitis C virus RNA-dependent RNA polymerase 总被引:14,自引:0,他引:14
Dhanak D Duffy KJ Johnston VK Lin-Goerke J Darcy M Shaw AN Gu B Silverman C Gates AT Nonnemacher MR Earnshaw DL Casper DJ Kaura A Baker A Greenwood C Gutshall LL Maley D DelVecchio A Macarron R Hofmann GA Alnoah Z Cheng HY Chan G Khandekar S Keenan RM Sarisky RT 《The Journal of biological chemistry》2002,277(41):38322-38327
The hepatitis C virus (HCV) NS5B protein encodes an RNA-dependent RNA polymerase (RdRp), the primary catalytic enzyme of the HCV replicase complex. We established a biochemical RNA synthesis assay, using purified recombinant NS5B lacking the C-terminal 21 amino acid residues, to identify potential polymerase inhibitors from a high throughput screen of the GlaxoSmithKline proprietary compound collection. The benzo-1,2,4-thiadiazine compound 1 was found to be a potent, highly specific inhibitor of NS5B. This agent interacts directly with the viral polymerase and inhibits RNA synthesis in a manner noncompetitive with respect to GTP. Furthermore, in the absence of an in vitro-reconstituted HCV replicase assay employing viral and host proteins, the ability of compound 1 to inhibit NS5B-directed viral RNA replication was determined using the Huh7 cell-based HCV replicon system. Compound 1 reduced viral RNA in replicon cells with an IC(50) of approximately 0.5 microm, suggesting that the inhibitor was able to access the perinuclear membrane and inhibit the polymerase activity in the context of a replicase complex. Preliminary structure-activity studies on compound 1 led to the identification of a modified inhibitor, compound 4, showing an improvement in both biochemical and cell-based potency. Lastly, data are presented suggesting that these compounds interfere with the formation of negative and positive strand progeny RNA by a similar mode of action. Investigations are ongoing to assess the potential utility of such agents in the treatment of chronic HCV disease. 相似文献
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Rosanna Tedesco Deping Chai Michael G. Darcy Dashyant Dhanak Duke M. Fitch Adam Gates Victor K. Johnston Richard M. Keenan Juili Lin-Goerke Robert T. Sarisky Antony N. Shaw Klara L. Valko Kenneth J. Wiggall Michael N. Zimmerman Kevin J. Duffy 《Bioorganic & medicinal chemistry letters》2009,19(15):4354-4358
Modification of the benzo rings of 3-(1,1-dioxo-2H-(1,2,4)-benzothiadiazin-3-yl)-4-hydroxy-2(1H)-quinolinones into heteroaromatic systems was investigated to enhance physicochemical properties and potency profile of this class of inhibitors. The synthesis and biological activity of the derived compounds is discussed. 相似文献
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Burton G Ku TW Carr TJ Kiesow T Sarisky RT Lin-Goerke J Baker A Earnshaw DL Hofmann GA Keenan RM Dhanak D 《Bioorganic & medicinal chemistry letters》2005,15(6):1553-1556
HTS of the compound collection for inhibition of the HCV RNA dependent RNA polymerase identified two 168 member N-acyl pyrrolidine combinatorial mixture hits. Deconvolution and expansion of these mixtures by solid phase synthesis to establish initial SAR and identify a potent inhibitor is reported. 相似文献
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