The Experts below are selected from a list of 150264 Experts worldwide ranked by ideXlab platform
Yaojiang Huang - One of the best experts on this subject based on the ideXlab platform.
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identification of potential key agents for targeting RNA dependent RNA Polymerase of sars cov 2 by integrated analysis and virtual drug screening
2020Co-Authors: Dan Han, Lei Sun, Shuang Liu, Yaojiang HuangAbstract:Background RNA-dependent RNA Polymerase (RdRp) is the key enzyme responsible for the SARS-CoV-2 replication process and catalyzes the synthesis of complementary minus strand RNA and genomic plus strand RNA, often recognized as good targets for antiviral drugs. Materials and methods A systematic screening of existing antiviral compounds, family analysis, conserved domain analysis, three-dimensional structure modeling, drug virtual screening, and bioassays were performed to identify agents that potentially targeted RNA-dependent RNA Polymerase of SARS-CoV-2. Results Four thousand nine hundred and forty seven antiviral lead compounds were selected and evaluated by systematic screening. Of these, 359 agents were screened by family analysis and conserved domain analysis. They were further analyzed by three-dimensional structure modeling, virtual drug screening, and bioassays. The results identified 102 agents with potential for repurposing to target the RNA-dependent RNA Polymerase of SARS-CoV-2. Conclusion This study identified 102 key agents with potential anti-SARS-CoV-2 RNA-dependent RNA Polymerase function and prospects of rapid clinical application for the treatment of COVID-19.
Hung Te Liu - One of the best experts on this subject based on the ideXlab platform.
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the potential chemical structure of anti sars cov 2 RNA dependent RNA Polymerase
2020Co-Authors: Jrhau Lung, Yushih Lin, Yaohsu Yang, Yu Lun Chou, Li Hsin Shu, Yuching Cheng, Hung Te LiuAbstract:An outbreak of coronavirus disease 2019 (COVID-19) occurred in Wuhan and it has rapidly spread to almost all parts of the world. For coronaviruses, RNA-dependent RNA Polymerase (RdRp) is an important Polymerase that catalyzes the replication of RNA from RNA template and is an attractive therapeutic target. In this study, we screened these chemical structures from traditional Chinese medicinal compounds proven to show antiviral activity in severe acute respiratory syndrome coronavirus (SARS-CoV) and the similar chemical structures through a molecular docking study to target RdRp of SARS-CoV-2, SARS-CoV, and Middle East respiratory syndrome coronavirus (MERS-CoV). We found that theaflavin has a lower idock score in the catalytic pocket of RdRp in SARS-CoV-2 (-9.11 kcal/mol), SARS-CoV (-8.03 kcal/mol), and MERS-CoV (-8.26 kcal/mol) from idock. To confirm the result, we discovered that theaflavin has lower binding energy of -8.8 kcal/mol when it docks in the catalytic pocket of SARS-CoV-2 RdRp by using the Blind Docking server. Regarding contact modes, hydrophobic interactions contribute significantly in binding and additional hydrogen bonds were found between theaflavin and RdRp. Moreover, one π-cation interaction was formed between theaflavin and Arg553 from the Blind Docking server. Our results suggest that theaflavin could be a potential SARS-CoV-2 RdRp inhibitor for further study.
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corrigendum to the potential chemical structure of anti sars cov 2 RNA dependent RNA Polymerase jouRNAl of medical virology 2020 92 6 693 697 10 1002 jmv 25761
2020Co-Authors: Jrhau Lung, Yushih Lin, Yaohsu Yang, Yu Lun Chou, Li Hsin Shu, Yuching Cheng, Hung Te LiuAbstract:The potential chemical structure of anti-SARS-CoV-2 RNA-dependent RNA Polymerase. The article to which this Corrigendum refers was published in JouRNAl of Medical Virology 92(6): 693 to 697 (https://onlinelibrary.wiley.com/doi/full/10.1002/jmv.25761). The corrigendum corrects protease to Polymerase in the “For coronaviruses, RNA-dependent. RNA Polymerase (RdRp) is an important protease that catalyzes the replication of RNA from RNA template and is an attractive therapeutic target.” of abstract section. The authors apologize for the error. 1.
Kevin J Duffy - One of the best experts on this subject based on the ideXlab platform.
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a highly efficient asymmetric synthesis of benzothiadiazine substituted tetramic acids potent inhibitors of hepatitis c virus RNA dependent RNA Polymerase
2005Co-Authors: Duke M Fitch, Karen A Evans, Deping Chai, Kevin J DuffyAbstract:[reaction: see text] An efficient two-pot, asymmetric synthesis of benzothiadiazine-substituted tetramic acids is reported. Starting from commercially available alpha-amino acids or esters, reductive amination followed by a novel one-pot amide bond formation/Dieckmann cyclization provided the desired products in high yield and optical purity. An analogous solid-phase approach to the same targets is also presented. These compounds were found to be potent inhibitors of hepatitis C virus RNA-dependent RNA Polymerase.
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resistance profile of a hepatitis c virus RNA dependent RNA Polymerase benzothiadiazine inhibitor
2003Co-Authors: Tammy T Nguyen, Lester L Gutshall, Victor K Johnston, Kevin J Duffy, Adam T Gates, Robert T SariskyAbstract:Recently, a benzo-1,2,4-thiadiazine antiviral agent (C 21 H 21 N 3 O 4 S; compound 4) was shown to be a potent, highly specific inhibitor of the primary catalytic enzyme of the hepatitis C virus (HCV) replicase complex. In this study, we selected for resistance to confirm the mechanism of action for compound 4 in HCV replicon cells. As expected, spontaneous mutations or fluidity in the HCV Polymerase (NS5B) coding sequence occurred upon routine passage of the HCV replicon cells in the absence of compound 4. After 1 month of culture in the presence of 10 μM compound 4, or 20 times the 50% inhibitory concentration of the replicon, replicon cells were almost 20-fold less susceptible to compound 4. Twenty-one NS5B cDNA clones were generated from the resistant replicon cells. Five mutations in the 21 NS5B clones were present at frequencies higher than that of control replicon cells, and no clone contained more than a single mutation within the Polymerase gene. RNA-dependent RNA Polymerase studies using purified recombinant NS5B containing these single point mutations allowed the identification of residue 414 as sufficient for biochemical resistance to compound 4. Further, the contribution of this residue to confer cell-based resistance to compound 4 was validated using a stable recombinant mutant replicon cell line which harbors a methionine-to-threonine change at residue 414. The potential for additional mutations in other nonstructural genes of HCV to contribute to the resistance profile of compound 4 is discussed.
Janet L Smith - One of the best experts on this subject based on the ideXlab platform.
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characterization of purified sindbis virus nsp4 RNA dependent RNA Polymerase activity in vitro
2009Co-Authors: Jon K Rubach, Brian R Wasik, Jonathan C Rupp, Richard J Kuhn, Richard W Hardy, Janet L SmithAbstract:The Sindbis virus RNA-dependent RNA Polymerase (nsP4) is responsible for the replication of the viral RNA genome. In infected cells, nsP4 is localized in a replication complex along with the other viral non-structural proteins. nsP4 has been difficult to homogenously purify from infected cells due to its interactions with the other replication proteins and the fact that its N-terminal residue, a tyrosine, causes the protein to be rapidly turned over in cells. We report the successful expression and purification of Sindbis nsP4 in a bacterial system, in which nsP4 is expressed as an N-terminal SUMO fusion protein. After purification the SUMO tag is removed, resulting in the isolation of full-length nsP4 possessing the authentic N-terminal tyrosine. This purified enzyme is able to produce minus-strand RNA de novo from plus-strand templates, as well as terminally add adenosine residues to the 3′ end of an RNA substrate. In the presence of the partially processed viral replicase polyprotein, P123, purified nsP4 is able to synthesize discrete template length minus-strand RNA products. Mutations in the 3′ CSE or poly(A) tail of viral template RNA prevent RNA synthesis by the replicase complex containing purified nsP4, consistent with previously reported template requirements for minus-strand RNA synthesis. Optimal reaction conditions were determined by investigating the effects of time, pH, and the concentrations of nsP4, P123 and magnesium on the synthesis of RNA.
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the structure of the RNA dependent RNA Polymerase from bovine viral diarrhea virus establishes the role of gtp in de novo initiation
2004Co-Authors: Kyung H Choi, Richard J Kuhn, Janet L Smith, James M Groarke, Dorothy C Young, Daniel C Pevear, Michael G RossmannAbstract:The bovine viral diarrhea virus (BVDV) RNA-dependent RNA Polymerase can initiate RNA replication by a de novo mechanism without a primer. The structure of BVDV Polymerase, determined to 2.9-A resolution, contains a unique N-terminal domain, in addition to the fingers, palm, and thumb domains common to other Polymerases. The structure of BVDV Polymerase complexed with GTP, which is required for de novo (primer-independent) initiation, shows that GTP binds adjacent to the initiation NTP, suggesting that the GTP mimics a vestigial RNA product. Comparison of five monomers in two different crystal forms showed conformational changes in the fingertip region and in the thumb domain that may help to translocate the RNA template and product strands during elongation. The putative binding sites of previously reported BVDV inhibitors are also discussed.
Yaohsu Yang - One of the best experts on this subject based on the ideXlab platform.
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the potential chemical structure of anti sars cov 2 RNA dependent RNA Polymerase
2020Co-Authors: Jrhau Lung, Yushih Lin, Yaohsu Yang, Yu Lun Chou, Li Hsin Shu, Yuching Cheng, Hung Te LiuAbstract:An outbreak of coronavirus disease 2019 (COVID-19) occurred in Wuhan and it has rapidly spread to almost all parts of the world. For coronaviruses, RNA-dependent RNA Polymerase (RdRp) is an important Polymerase that catalyzes the replication of RNA from RNA template and is an attractive therapeutic target. In this study, we screened these chemical structures from traditional Chinese medicinal compounds proven to show antiviral activity in severe acute respiratory syndrome coronavirus (SARS-CoV) and the similar chemical structures through a molecular docking study to target RdRp of SARS-CoV-2, SARS-CoV, and Middle East respiratory syndrome coronavirus (MERS-CoV). We found that theaflavin has a lower idock score in the catalytic pocket of RdRp in SARS-CoV-2 (-9.11 kcal/mol), SARS-CoV (-8.03 kcal/mol), and MERS-CoV (-8.26 kcal/mol) from idock. To confirm the result, we discovered that theaflavin has lower binding energy of -8.8 kcal/mol when it docks in the catalytic pocket of SARS-CoV-2 RdRp by using the Blind Docking server. Regarding contact modes, hydrophobic interactions contribute significantly in binding and additional hydrogen bonds were found between theaflavin and RdRp. Moreover, one π-cation interaction was formed between theaflavin and Arg553 from the Blind Docking server. Our results suggest that theaflavin could be a potential SARS-CoV-2 RdRp inhibitor for further study.
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corrigendum to the potential chemical structure of anti sars cov 2 RNA dependent RNA Polymerase jouRNAl of medical virology 2020 92 6 693 697 10 1002 jmv 25761
2020Co-Authors: Jrhau Lung, Yushih Lin, Yaohsu Yang, Yu Lun Chou, Li Hsin Shu, Yuching Cheng, Hung Te LiuAbstract:The potential chemical structure of anti-SARS-CoV-2 RNA-dependent RNA Polymerase. The article to which this Corrigendum refers was published in JouRNAl of Medical Virology 92(6): 693 to 697 (https://onlinelibrary.wiley.com/doi/full/10.1002/jmv.25761). The corrigendum corrects protease to Polymerase in the “For coronaviruses, RNA-dependent. RNA Polymerase (RdRp) is an important protease that catalyzes the replication of RNA from RNA template and is an attractive therapeutic target.” of abstract section. The authors apologize for the error. 1.
