In silico characterization of the NiRAN domain of RNA-dependent RNA polymerase provides insights into a potential therapeutic target against SARS-CoV2

Dwivedy, Abhisek; Mariadasse, Richard; Ahmed, Mohammed; Kar, Deepsikha; Jeyakanthan, Jeyaraman; Biswal, B.K.

doi:10.31219/osf.io/wd6zu

Cited by 4 publications

(4 citation statements)

References 76 publications

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“…We also confirmed the anti-SARS-CoV-2 activity of five compounds that were reported as virtual screening hits but had yet to be confirmed experimentally, including methdilazine by an AI prediction algorithm ( Grzybowski et al, 2020 ), GMC 2-113 by a virtual screen of RNA dependent RNA polymerase (RdRP) ( Dwivedy et al, 2020 ), maprotiline by a main protease docking ( Chauhan, 2020 ), deserpidine by a NPS-16 docking ( Jiang et al, 2020 ), and flunarizine by a spike protein docking screen ( Chernyshev, 2020 ). Our data supports the utility of these emerging technologies and the field of AI for advancing drug development.…”

Section: Discussionsupporting

confidence: 66%

Drug Repurposing Screen for Compounds Inhibiting the Cytopathic Effect of SARS-CoV-2

et al. 2021

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Drug repurposing is a rapid approach to identify therapeutics for the treatment of emerging infectious diseases such as COVID-19. To address the urgent need for treatment options, we carried out a quantitative high-throughput screen using a SARS-CoV-2 cytopathic assay with a compound collection of 8,810 approved and investigational drugs, mechanism-based bioactive compounds, and natural products. Three hundred and nineteen compounds with anti-SARS-CoV-2 activities were identified and confirmed, including 91 approved drugs and 49 investigational drugs. The anti-SARS-CoV-2 activities of 230 of these confirmed compounds, of which 38 are approved drugs, have not been previously reported. Chlorprothixene, methotrimeprazine, and piperacetazine were the three most potent FDA-approved drugs with anti-SARS-CoV-2 activities. These three compounds have not been previously reported to have anti-SARS-CoV-2 activities, although their antiviral activities against SARS-CoV and Ebola virus have been reported. These results demonstrate that this comprehensive data set is a useful resource for drug repurposing efforts, including design of new drug combinations for clinical trials for SARS-CoV-2.

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Section: Discussionsupporting

confidence: 66%

Drug Repurposing Screen for Compounds Inhibiting the Cytopathic Effect of SARS-CoV-2

et al. 2021

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“…We also confirmed the anti-SARS-CoV-2 activity of 5 compounds that were reported as virtual screening hits but had yet to be confirmed experimentally, including methdilazine by an AI prediction algorithm (Grzybowski et al, 2020), GMC 2-113 by a virtual screen of RNA dependent RNA polymerase (RdRP) (Dwivedy et al, 2020), maprotiline by a main protease docking (Chauhan, 2020), deserpidine by a NPS-16 docking (Jiang et al, 2020), and flunarizine by a spike protein docking screen (Chernyshev, 2020). Our data supports the utility of these emerging technologies and the field of AI for advancing drug development.…”

Section: Discussionsupporting

confidence: 60%

Drug Repurposing Screen for Compounds Inhibiting the Cytopathic Effect of SARS-CoV-2

Chen

Shinn

Itkin

et al. 2020

Preprint

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Drug repurposing is a rapid approach to identifying therapeutics for the treatment of emerging infectious diseases such as COVID-19. To address the urgent need for treatment options, we carried out a quantitative high-throughput screen using a SARS-CoV-2 cytopathic assay with a compound collection of 8,810 approved and investigational drugs, mechanism-based bioactive compounds, and natural products. Three hundred and nineteen compounds with anti-SARS-CoV-2 activities were identified and confirmed, including 91 approved drug and 49 investigational drugs. Among these confirmed compounds, the anti-SARS-CoV-2 activities of 230 compounds, including 38 approved drugs, have not been previously reported. Chlorprothixene, methotrimeprazine, and piperacetazine were the three most potent FDA approved drugs with anti-SARS-CoV-2 activities. These three compounds have not been previously reported to have anti-SARS-CoV-2 activities, although their antiviral activities against SARS-CoV and Ebola virus have been reported. These results demonstrate that this comprehensive data set of drug repurposing screen for SARS-CoV-2 is useful for drug repurposing efforts including design of new drug combinations for clinical trials.

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“…CC-BY 4.0 International license available under a (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made The copyright holder for this preprint this version posted March 18, 2021. ; https://doi.org/10.1101/2021.03.17.435913 doi: bioRxiv preprint 13 target for future antiviral drugs as it could be targeted by nucleotide analogues, and in silico studies propose that certain kinase inhibitors may be able to bind to the NiRAN domain (41).…”

Section: Discussionmentioning

confidence: 99%

“…We also find that the drug inhibits the NiRAN domain GTase reaction with a much lower IC 50 , which could be due to mechanistic differences in the GTase reaction compared to full-length nsp12, or because remdesivir triphosphate binding to the nsp12 RdRP domain reduces efficacy. The SARS-CoV-2 nsp12 NiRAN domain is an attractive target for future antiviral drugs as it could be targeted by nucleotide analogues, and in silico studies propose that certain kinase inhibitors may be able to bind to the NiRAN domain(41). The GTase activity assay we have established here could function as a useful tool to assess the potency of these compounds.…”

Section: Discussionmentioning

confidence: 99%

Identification of guanylyltransferase activity in the SARS-CoV-2 RNA polymerase

Walker

Fan

Keown

et al. 2021

Preprint

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SARS-CoV-2 is a positive-sense RNA virus that is responsible for the ongoing Coronavirus Disease 2019 (COVID-19) pandemic, which continues to cause significant morbidity, mortality and economic strain. SARS-CoV-2 can cause severe respiratory disease and death in humans, highlighting the need for effective antiviral therapies. The RNA synthesis machinery of SARS-CoV-2 is an ideal drug target and consists of non-structural protein 12 (nsp12), which is directly responsible for RNA synthesis, and numerous co-factors that are involved in RNA proofreading and 5’ capping of viral mRNAs. The formation of the 5’ cap-1 structure is known to require a guanylyltransferase (GTase) as well as 5’ triphosphatase and methyltransferase activities. However, the mechanism of SARS-CoV-2 mRNA capping remains poorly understood. Here we show that the SARS-CoV-2 RNA polymerase nsp12 functions as a GTase. We characterise this GTase activity and find that the nsp12 NiRAN (nidovirus RdRP-associated nucleotidyltransferase) domain is responsible for carrying out the addition of a GTP nucleotide to the 5’ end of viral RNA via a 5’ to 5’ triphosphate linkage. We also show that remdesivir triphosphate, the active form of the antiviral drug remdesivir, inhibits the SARS-CoV-2 GTase reaction as efficiently as RNA polymerase activity. These data improve understanding of coronavirus mRNA cap synthesis and highlight a new target for novel or repurposed antiviral drugs against SARS-CoV-2.ImportanceSARS-CoV-2 is a respiratory RNA virus responsible for the Coronavirus Disease 2019 (COVID-19) pandemic. Coronaviruses encode an RNA polymerase which, in combination with other viral proteins, is responsible for synthesising capped viral mRNA. mRNA cap synthesis requires a guanylyltransferase enzyme; here we show that the SARS-CoV-2 guanylyltransferase is located in the viral RNA polymerase, and we identify the protein domain responsible for guanylyltransferase activity. Furthermore we demonstrate that remdesivir triphosphate, the active metabolite of remdesivir, inhibits both the guanylyltransferase and RNA polymerase functions of the SARS-CoV-2 RNA polymerase. These findings improve understanding of the coronavirus mRNA cap synthesis mechanism, in addition to highlighting a new target for the development of therapeutics to treat SARS-CoV-2 infection.

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In silico characterization of the NiRAN domain of RNA-dependent RNA polymerase provides insights into a potential therapeutic target against SARS-CoV2

Cited by 4 publications

References 76 publications

Drug Repurposing Screen for Compounds Inhibiting the Cytopathic Effect of SARS-CoV-2

Drug Repurposing Screen for Compounds Inhibiting the Cytopathic Effect of SARS-CoV-2

Drug Repurposing Screen for Compounds Inhibiting the Cytopathic Effect of SARS-CoV-2

Identification of guanylyltransferase activity in the SARS-CoV-2 RNA polymerase

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