[439] ADDITIVE TO SYNERGISTIC ANTIVIRAL EFFECTS OF AN NS3/4A PROTEASE INHIBITOR (ITMN-191) AND AN NS5B RNA-DEPENDENT RNA POLYMERASE INHIBITOR (R1479) IN AN HCV REPLICON SYSTEM

SARS-CoV-2 has caused an extensive pandemic of COVID-19 all around the world. Key viral enzymes are suitable molecular targets for the development of new antivirals against SARS-CoV-2 which could represent potential treatments of the corresponding disease. With respect to its essential role in the replication of viral RNA, RNA-dependent RNA polymerase (RdRp) is one of the prime targets. HeE1-2Tyr and related derivatives were originally discovered as inhibitors of the RdRp of flaviviruses. Here, we present that these pyridobenzothiazole derivatives also significantly inhibit SARS-CoV-2 RdRp, as demonstrated using both polymerase- and cell-based antiviral assays.

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From the Cover: Investigative Nonclinical Cardiovascular Safety and Toxicology Studies with BMS-986094, an NS5b RNA-Dependent RNA Polymerase Inhibitor

Toxicological Sciences ◽

10.1093/toxsci/kfw211 ◽

2016 ◽

Vol 155 (2) ◽

pp. 348-362 ◽

Cited By ~ 2

Author(s):

Michael Gill ◽

Kristen Horn ◽

James Hennan ◽

Randy White ◽

Denise Bounous ◽

...

Keyword(s):

Rna Polymerase ◽

Cardiovascular Safety ◽

Rna Dependent Rna Polymerase ◽

Polymerase Inhibitor

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Response to the comments received on article “Efficacy and safety of favipiravir, an oral RNA-dependent RNA polymerase inhibitor, in mild-to-moderate COVID-19: A randomized, comparative, open-label, multicenter, phase 3 clinical trial” by Udwadia et al

International Journal of Infectious Diseases ◽

10.1016/j.ijid.2021.02.028 ◽

2021 ◽

Vol 105 ◽

pp. 686-687

Author(s):

Zarir F. Udwadia ◽

Hanmant Barkate ◽

Saiprasad Patil ◽

Shabbir Rangwala ◽

Wen Wu ◽

...

Keyword(s):

Clinical Trial ◽

Rna Polymerase ◽

Efficacy And Safety ◽

Open Label ◽

Rna Dependent Rna Polymerase ◽

Phase 3 ◽

Multicenter Phase ◽

Polymerase Inhibitor

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An RNA-dependent RNA polymerase inhibitor for tick-borne encephalitis virus

Virology ◽

10.1016/j.virol.2020.03.006 ◽

2020 ◽

Vol 546 ◽

pp. 13-19

Author(s):

Varun Gejji ◽

Pavel Svoboda ◽

Michal Stefanik ◽

Haoqi Wang ◽

Jiri Salat ◽

...

Keyword(s):

Rna Polymerase ◽

Encephalitis Virus ◽

Rna Dependent Rna Polymerase ◽

Tick Borne Encephalitis ◽

Polymerase Inhibitor ◽

Tick Borne Encephalitis Virus

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Early combination treatment with existing HIV antivirals: an effective treatment for COVID-19?

10.21203/rs.3.rs-35791/v1 ◽

2020 ◽

Author(s):

Roberto Nico Dallocchio ◽

Alessandro Dessì ◽

Andrea De Vito ◽

Giovanna Delogu ◽

Pier Andrea ◽

...

Keyword(s):

Clinical Trials ◽

Molecular Docking ◽

Severe Acute Respiratory Syndrome ◽

Rna Polymerase ◽

Protease Inhibitor ◽

Combination Treatment ◽

Binding Sites ◽

Nucleoside Analogues ◽

Rna Dependent Rna Polymerase ◽

Protein Pocket

Abstract Since no effective therapy exists, we aimed to test existing HIV antivirals for combination treatment of Coronavirus disease 19 (COVID-19). Our molecular docking findings suggest that lopinavir, ritonavir, darunavir, and atazanavir activated interactions with the key binding sites of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) protease with a better Ki for lopinavir, ritonavir, and darunavir. Furthermore, we evidenced the ability of remdesivir, tenofovir, emtricitabine, and lamivudine to be incorporated in SARS-CoV-2 RNA-dependent RNA polymerase in the same protein pocket where poses the corresponding natural nucleoside substrates with comparable Ki and activating similar interactions. In principle, the four antiviral nucleotides might be used effectively against SARS-CoV-2. The combination of a protease inhibitor and two nucleoside analogues should be evaluated in clinical trials for the treatment of COVID-19.

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Structural basis for the inhibition of the SARS-CoV-2 RNA-dependent RNA polymerase by favipiravir-RTP

10.1101/2020.10.21.347690 ◽

2020 ◽

Author(s):

Katerina Naydenova ◽

Kyle W. Muir ◽

Long-Fei Wu ◽

Ziguo Zhang ◽

Francesca Coscia ◽

...

Keyword(s):

Rna Polymerase ◽

Binding Pocket ◽

Binding Mode ◽

Polymerase Activity ◽

Catalytic Site ◽

Structural Basis ◽

Limited Information ◽

Rna Dependent Rna Polymerase ◽

Polymerase Inhibitor ◽

Ribonucleoside Triphosphate

AbstractThe RNA polymerase inhibitor, favipiravir, is currently in clinical trials as a treatment for infection with SARS-CoV-2, despite limited information about the molecular basis for its activity. Here we report the structure of favipiravir ribonucleoside triphosphate (favipiravir-RTP) in complex with the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) bound to a template:primer RNA duplex, determined by electron cryomicroscopy (cryoEM) to a resolution of 2.5 Å. The structure shows clear evidence for the inhibitor at the catalytic site of the enzyme, and resolves the conformation of key side chains and ions surrounding the binding pocket. Polymerase activity assays indicate that the inhibitor is weakly incorporated into the RNA primer strand, and suppresses RNA replication in the presence of natural nucleotides. The structure reveals an unusual, non-productive binding mode of favipiravir-RTP at the catalytic site of SARS-CoV-2 RdRp which explains its low rate of incorporation into the RNA primer strand. Together, these findings inform current and future efforts to develop polymerase inhibitors for SARS coronaviruses.

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