Potential Inhibition of COVID-19 RNA-dependent RNA Polymerase by Hepatitis C Virus Non-nucleoside Inhibitors: An In-silico Perspective

2020 ◽  
Vol 17 ◽  
Author(s):  
Yee Siew Choong ◽  
Theam Soon Lim ◽  
Hanyun Liu ◽  
Rubin Jiang ◽  
Zimu Cai ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Rna Polymerase ◽  
Binding Sites ◽  
Homology Modelling ◽  
Clinical Importance ◽  
Rna Dependent Rna Polymerase ◽  
Nucleoside Inhibitors

Background: Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a novel member of the genus betacoronavirus in the Coronaviridae family. It has been identified as the causative agent of coronavirus disease 2019 (COVID-19) spreading rapidly in Asia, America and Europe. Like some other RNA viruses, RNA replication and transcription of SARS-CoV-2 relies on its RNA-dependent RNA polymerase (RdRP), which is a therapeutic target of clinical importance. Crystal structure of SARS-CoV-2 that was solved recently (PDB ID 6M71) with some missing residues. Objective: We used SARS-CoV-2 RdRP as a target protein to screen for possible chemical molecules with potential antiviral effects. Method: Here we modelled the missing residues 896-905 via homology modelling and then analysed the interactions of Hepatitis C virus allosteric non-nucleoside inhibitors (NNIs) in the reported NNIs binding sites in SARS-CoV-2 RdRP. Results and Discussion: We found that MK-3281, filibuvir, setrobuvir and dasabuvir might be able to inhibit SARS-CoV-2 RdRP based on their binding affinities in the respective binding sites. Conclusion: Further in vitro and in vivo experimental research will be carried out to evaluate their effectiveness in COVID19 treatment in the near future.

scholarly journals Interaction with a Ubiquitin-Like Protein Enhances the Ubiquitination and Degradation of Hepatitis C Virus RNA-Dependent RNA Polymerase

2003 ◽  
Vol 77 (7) ◽  
pp. 4149-4159 ◽  
Author(s):  
Lu Gao ◽  
Hong Tu ◽  
Stephanie T. Shi ◽  
Ki-Jeong Lee ◽  
Miyuki Asanaka ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Rna Polymerase ◽  
Hcv Rna ◽  
Rna Dependent Rna Polymerase ◽  
Subgenomic Replicon ◽  
C Terminus ◽  
Huh7 Cells

ABSTRACT To identify potential cellular regulators of hepatitis C virus (HCV) RNA-dependent RNA polymerase (NS5B), we searched for cellular proteins interacting with NS5B protein by yeast two-hybrid screening of a human hepatocyte cDNA library. We identified a ubiquitin-like protein, hPLIC1 (for human homolog 1 of protein linking intergrin-associated protein and cytoskeleton), which is expressed in the liver (M. F. Kleijnen, A. H. Shih, P. Zhou, S. Kumar, R. E. Soccio, N. L. Kedersha, G. Gill, and P. M. Howley, Mol. Cell 6: 409-419, 2000). In vitro binding assays and in vivo coimmunoprecipitation studies confirmed the interaction between hPLIC1 and NS5B, which occurred through the ubiquitin-associated domain at the C terminus of the hPLIC1 protein. As hPLICs have been shown to physically associate with two E3 ubiquitin protein ligases as well as proteasomes (Kleijnen et al., Mol. Cell 6: 409-419, 2000), we investigated whether the stability and posttranslational modification of NS5B were affected by hPLIC1. A pulse-chase labeling experiment revealed that overexpression of hPLIC1, but not the mutant lacking the NS5B-binding domain, significantly shortened the half-life of NS5B and enhanced the polyubiquitination of NS5B. Furthermore, in Huh7 cells that express an HCV subgenomic replicon, the amounts of both NS5B and the replicon RNA were reduced by overexpression of hPLIC1. Thus, hPLIC1 may be a regulator of HCV RNA replication through interaction with NS5B.

New Non-nucleoside Inhibitors of Hepatitis C Virus RNA-Dependent RNA Polymerase

2004 ◽  
Vol 69 (7) ◽  
pp. 782-788 ◽  
Author(s):  
A. V. Ivanov ◽  
M. V. Kozlov ◽  
A. O. Kuzyakin ◽  
D. A. Kostyuk ◽  
V. L. Tunitskaya ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Rna Polymerase ◽  
Hepatitis C Virus Rna ◽  
Rna Dependent Rna Polymerase ◽  
Virus Rna ◽  
Nucleoside Inhibitors

scholarly journals Crystal Structures of the RNA-dependent RNA Polymerase Genotype 2a of Hepatitis C Virus Reveal Two Conformations and Suggest Mechanisms of Inhibition by Non-nucleoside Inhibitors

2005 ◽  
Vol 280 (18) ◽  
pp. 18202-18210 ◽  
Author(s):  
Bichitra K. Biswal ◽  
Maia M. Cherney ◽  
Meitian Wang ◽  
Laval Chan ◽  
Constantin G. Yannopoulos ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Rna Polymerase ◽  
Crystal Structures ◽  
Rna Dependent Rna Polymerase ◽  
Nucleoside Inhibitors

Hepatitis C Virus NS5A Protein In Vitro Modulates Template Selection by the RNA-dependent RNA Polymerase

2009 ◽  
Vol 82 (2) ◽  
pp. A28-A29
Author(s):  
Olga Ivanova ◽  
Vera Tunitskaya ◽  
Alexander Ivanov ◽  
Vladimir Mitkevich ◽  
Vladimir Prassolov ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Rna Polymerase ◽  
Rna Dependent Rna Polymerase ◽  
Ns5a Protein ◽  
Template Selection

Nucleoside, Nucleotide, and Non-Nucleoside Inhibitors of Hepatitis C Virus NS5B RNA-Dependent RNA-Polymerase

2012 ◽  
Vol 55 (6) ◽  
pp. 2481-2531 ◽  
Author(s):  
Michael J. Sofia ◽  
Wonsuk Chang ◽  
Phillip A. Furman ◽  
Ralph T. Mosley ◽  
Bruce S. Ross
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Rna Polymerase ◽  
Rna Dependent Rna Polymerase ◽  
Nucleoside Inhibitors

Novel 4-Thiazolidinones as Non-Nucleoside Inhibitors of Hepatitis C Virus NS5B RNA-Dependent RNA Polymerase

2014 ◽  
Vol 348 (1) ◽  
pp. 10-22 ◽  
Author(s):  
Gizem Çakır ◽  
İlkay Küçükgüzel ◽  
Rupa Guhamazumder ◽  
Esra Tatar ◽  
Dinesh Manvar ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Rna Polymerase ◽  
Rna Dependent Rna Polymerase ◽  
Nucleoside Inhibitors

Correction to Nucleoside, Nucleotide, and Non-Nucleoside Inhibitors of Hepatitis C Virus NS5B RNA-Dependent RNA-Polymerase

2017 ◽  
Vol 60 (7) ◽  
pp. 3219-3219
Author(s):  
Michael J. Sofia ◽  
Wonsuk Chang ◽  
Phillip A. Furman ◽  
Ralph T. Mosley ◽  
Bruce S. Ross
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Rna Polymerase ◽  
Rna Dependent Rna Polymerase ◽  
Nucleoside Inhibitors

scholarly journals In vitro selection of RNA aptamers that bind the RNA-dependent RNA polymerase of hepatitis C virus: A possible role of GC-rich RNA motifs in NS5B binding

Virology ◽  
2009 ◽  
Vol 388 (1) ◽  
pp. 91-102 ◽  
Author(s):  
Hiroshi Kanamori ◽  
Kazuhito Yuhashi ◽  
Yasutoshi Uchiyama ◽  
Tatsuhiko Kodama ◽  
Shin Ohnishi
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Rna Polymerase ◽  
In Vitro Selection ◽  
Rna Aptamers ◽  
Rna Dependent Rna Polymerase ◽  
Rna Motifs ◽  
Selection Of

scholarly journals Evidence for Internal Initiation of RNA Synthesis by the Hepatitis C Virus RNA-Dependent RNA Polymerase NS5B In Cellulo

2019 ◽  
Vol 93 (19) ◽  
Author(s):  
Philipp Schult ◽  
Maren Nattermann ◽  
Chris Lauber ◽  
Stefan Seitz ◽  
Volker Lohmann
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Rna Polymerase ◽  
Rna Synthesis ◽  
Rna Viruses ◽  
Rna Replication ◽  
Rna Dependent Rna Polymerase ◽  
Internal Initiation ◽  
Positive Strand Rna

ABSTRACT Initiation of RNA synthesis by the hepatitis C virus (HCV) RNA-dependent RNA polymerase (RdRp) NS5B has been extensively studied in vitro and in cellulo. Intracellular replication is thought to rely exclusively on terminal de novo initiation, as it conserves all genetic information of the genome. In vitro, however, additional modes of initiation have been observed. In this study, we aimed to clarify whether the intracellular environment allows for internal initiation of RNA replication by the HCV replicase. We used a dual luciferase replicon harboring a terminal and an internal copy of the viral genomic 5′ untranslated region, which was anticipated to support noncanonical initiation. Indeed, a shorter RNA species was detected by Northern blotting with low frequency, depending on the length and sequence composition upstream of the internal initiation site. By introducing mutations at either site, we furthermore established that internal and terminal initiation shared identical sequence requirements. Importantly, lethal point mutations at the terminal site resulted exclusively in truncated replicons. In contrast, the same mutations at the internal site abrogated internal initiation, suggesting a competitive selection of initiation sites, rather than recombination or template-switching events. In conclusion, our data indicate that the HCV replicase is capable of internal initiation in its natural environment, although functional replication likely requires only terminal initiation. Since many other positive-strand RNA viruses generate subgenomic messenger RNAs during their replication cycle, we surmise that their capability for internal initiation is a common and conserved feature of viral RdRps. IMPORTANCE Many aspects of viral RNA replication of hepatitis C virus (HCV) are still poorly understood. The process of RNA synthesis is driven by the RNA-dependent RNA polymerase (RdRp) NS5B. Most mechanistic studies on NS5B so far were performed with in vitro systems using isolated recombinant polymerase. In this study, we present a replicon model, which allows the intracellular assessment of noncanonical modes of initiation by the full HCV replicase. Our results add to the understanding of the biochemical processes underlying initiation of RNA synthesis by NS5B by the discovery of internal initiation in cellulo. Moreover, they validate observations made in vitro, showing that the viral polymerase acts very similarly in isolation and in complex with other viral and host proteins. Finally, these observations provide clues about the evolution of RdRps of positive-strand RNA viruses, which might contain the intrinsic ability to initiate internally.

scholarly journals Revealing Anti-viral Potential of Bio-active Therapeutics Targeting SARS-CoV2- polymerase (RdRp) in Combating COVID-19: Molecular Investigation on Indian Traditional Medicines

2020 ◽  
Author(s):  
Dhanasekaran Sivaraman ◽  
Puspharaj selvadoss Pradeep
Keyword(s):  
Rna Polymerase ◽  
Clinical Importance ◽  
Biologically Active ◽  
In Vivo Studies ◽  
Rna Dependent Rna Polymerase ◽  
Standard Drug ◽  
Traditional Medicines ◽  
Clinical Recommendation

Spread of severe acute respiratory syndrome coronavirus (SARS-CoV-2) made a historic transition between December 2019 to March 2020. In the present scenario SARS-CoV-2 as becomes a major burden on public health and economic stability of societies around the globe. From the substantial evidences gained from the pandemic of SARS-CoV-2 and MERS-CoV (Middle East respiratory syndrome coronavirus), scientists and clinicians strongly believes that these pathogenic viruses share common homology of some biologically active enzymes which includes RNA-dependent RNA polymerase (RdRP), 3-chymotrypsin-like protease (3CLpro), papain-like protease (PLpro) etc. RdRP relatively grabs higher level of clinical importance in comparison with other enzyme target. Indian system of traditional medicine pioneering the therapy towards infectious disease since several centuries. In view of this potential therapeutic leads from some of the Indian medicines along with standard drug favipiravir subjected to docking investigation targeting SARS-CoV-2- RNA dependent RNA polymerase (RdRp). Residual proximity analysis reveals 18 out of 28 compounds reveals potential binding affinity of about 100% with the target amino acid residue (618 ASP, 760 ASP,761 ASP), 7 out of 28 reveals 75% binding efficacy and 3 out of 28 reveals 25% binding efficacy with that of the target residue. Hence further clinical validation may be warranted with proper in-vitro and in-vivo studies prior to the clinical recommendation in treating COVID-19 patient’s.

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