Hepatitis C Virus NS5B RNA-Dependent RNA Polymerase Inhibitor

Dash, Srikanta; Aydın, Yücel; Stephens, Christopher M.

doi:10.1016/b978-0-12-815422-9.00008-5

Cited by 6 publications

(3 citation statements)

References 104 publications

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“…Nucleoside analogs commonly target viral replication, particularly viral polymerase [ 8 ], and they have succeeded clinically in treatment of multiple viral infectious diseases [ 9 ]. For example, hepatitis C virus (HCV) RdRp inhibitors have achieved high success rates in clinical treatment [ 10 ]. Ribavirin triphosphate inhibits HCV RdRp [ 11 ], and sofosbuvir is a nucleotide analog that is inserted into HCV RNA by HCV RdRp, acting as a chain terminator [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

A Cell-Based Reporter Assay for Screening Inhibitors of MERS Coronavirus RNA-Dependent RNA Polymerase Activity

Min

Kim

Kwon

et al. 2020

JCM

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Severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and coronavirus disease 2019 (COVID-19) are emerging zoonotic diseases caused by coronavirus (CoV) infections. The viral RNA-dependent RNA polymerase (RdRp) has been suggested as a valuable target for antiviral therapeutics because the sequence homology of CoV RdRp is highly conserved. We established a cell-based reporter assay for MERS-CoV RdRp activity to test viral polymerase inhibitors. The cell-based reporter system was composed of the bicistronic reporter construct and the MERS-CoV nsp12 plasmid construct. Among the tested nine viral polymerase inhibitors, ribavirin, sofosbuvir, favipiravir, lamivudine, zidovudine, valacyclovir, vidarabine, dasabuvir, and remdesivir, only remdesivir exhibited a dose-dependent inhibition. Meanwhile, the Z-factor and Z′-factor of this assay for screening inhibitors of MERS-CoV RdRp activity were 0.778 and 0.782, respectively. Ribavirin and favipiravir did not inhibit the MERS-CoV RdRp activity, and non-nucleoside HCV RdRp inhibitor, dasabuvir, partially inhibited MERS-CoV RdRp activity. Taken together, the cell-based reporter assay for MERS-CoV RdRp activity confirmed remdesivir as a direct inhibitor of MERS-CoV RdRp in cells. A cell-based MERS-CoV RdRp activity reporter assay is reliable and accurate for screening MERS-CoV RdRp-specific inhibitors. It may provide a valuable platform for developing antiviral drugs for emerging CoV infections.

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Section: Introductionmentioning

confidence: 99%

A Cell-Based Reporter Assay for Screening Inhibitors of MERS Coronavirus RNA-Dependent RNA Polymerase Activity

Min

Kim

Kwon

et al. 2020

JCM

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“…Most of these antiviral nucleosides act by targeting the viral polymerases. [5][6][7][8] When incorporated in the viral nucleic acid these inhibitors may act as obligate chain terminators (such as 3ʹ-deoxy nucleosides) or through delayed chain terminators when nucleic acid synthesis is inhibited after incorporation of n bases after the antiviral nucleotide. The high affinity of some of these inhibitors to specific viral polymerases can narrow the antiviral spectrum of such molecules.…”

Section: Introductionmentioning

confidence: 99%

The synergy between nucleotide biosynthesis inhibitors and antiviral nucleosides: New opportunities against viral infections?

Miranda

2022

Archiv der Pharmazie

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5ʹ-Phosphorylated nucleoside derivatives are molecules that can be found in all living organisms and viruses. Over the last century, the development of structural analogs that could disrupt the transcription and translation of genetic information culminated in the development of clinically relevant anticancer and antiviral drugs.However, clinically effective broad-spectrum antiviral compounds or treatments are lacking. This viewpoint proposes that molecules that inhibit nucleotide biosynthesis may sensitize virus-infected cells toward direct-acting antiviral nucleosides. Such potentially synergistic combinations might allow the repurposing of drugs, leading to the development of new combination therapies.

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“…RNA-dependent RNA polymerase (RdRP) is a nonstructural protein that is crucial for SARS-CoV-2 replication ( Gaurav & Al-Nema, 2019 ). RdRP is a significant drug target against CoVs, implemented for the discovery of new antivirals against MERS CoV ( Gordon et al, 2020 ), dengue ( Shimizu et al, 2019 ), Zika ( Ahmad et al, 2020 ), influenza A ( Niazi et al, 2019 ) and hepatitis C viruses ( Dash, Aydin & Stephens, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

Repurposing FDA-approved phytomedicines, natural products, antivirals and cell protectives against SARS-CoV-2 (COVID-19) RNA-dependent RNA polymerase

Kandeel

Kitade

Al-Mubarak

2020

PeerJ

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Following the recent emergence of SARS-CoV-2 or coronavirus disease 2019 (COVID-19), drug discovery and vaccine design to combat this fatal infection are critical. In this study, an essential enzyme in the SARS-CoV-2 replication machinery, RNA-dependent RNA polymerase (RDRP), is targeted in a virtual screening assay using a set of 1,664 FDA-approved drugs, including sets of botanical and synthetic derivatives. A set of 22 drugs showed a high docking score of >−7. Notably, approximately one-third of the top hits were either from natural products or biological molecules. The FDA-approved phytochemicals were sennosides, digoxin, asiaticoside, glycyrrhizin, neohesperidin, taxifolin, quercetin and aloin. These approved natural products and phytochemicals are used as general tonics, antioxidants, cell protectives, and immune stimulants (nadid, thymopentin, asiaticoside, glycyrrhizin) and in other miscellaneous systemic or topical applications. A comprehensive analysis was conducted on standard precision and extra precision docking, two-step molecular dynamics simulations, binding energy calculations and a post dynamics analysis. The results reveal that two drugs, docetaxel and neohesperidin, showed strong binding profiles with SARS CoV-2 RdRP. These results can be used as a primer for further drug discovery studies in the treatment of COVID-19. This initiative repurposes safe FDA-approved drugs against COVID-19 RdRP, providing a rapid channel for the discovery and application of new anti-CoV therapeutics.

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Hepatitis C Virus NS5B RNA-Dependent RNA Polymerase Inhibitor

Cited by 6 publications

References 104 publications

A Cell-Based Reporter Assay for Screening Inhibitors of MERS Coronavirus RNA-Dependent RNA Polymerase Activity

A Cell-Based Reporter Assay for Screening Inhibitors of MERS Coronavirus RNA-Dependent RNA Polymerase Activity

The synergy between nucleotide biosynthesis inhibitors and antiviral nucleosides: New opportunities against viral infections?

Repurposing FDA-approved phytomedicines, natural products, antivirals and cell protectives against SARS-CoV-2 (COVID-19) RNA-dependent RNA polymerase

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