Influenza Polymerase Inhibitors: Mechanisms of Action and Resistance

Takashita, Emi

doi:10.1101/cshperspect.a038687

Cited by 46 publications

(35 citation statements)

References 55 publications

(68 reference statements)

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“…Favipiravir (6-fluoro-3-hydroxypyrazine-2-carboxamide, Avigan ® ) was initially developed as an antiviral agent for the treatment of influenza. The mechanism of favipiravir is inhibition of viral RNA replication by inhibition of RdRp formed as a complex of PA protein, PB1 protein, and PB2 protein [ 8 , 9 , 10 , 11 ]. Subsequently, favipiravir was reported to have similar activity against RdRp proteins from RNA viruses other than influenza and showed efficacy for treatment of ebolavirus disease (EVD), Lassa fever, and norovirus infections [ 12 , 13 , 14 ].…”

Section: Introductionmentioning

confidence: 99%

Detailed Molecular Interactions of Favipiravir with SARS-CoV-2, SARS-CoV, MERS-CoV, and Influenza Virus Polymerases In Silico

et al. 2020

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Favipiravir was initially developed as an antiviral drug against influenza and is currently used in clinical trials against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection (COVID-19). This agent is presumably involved in RNA chain termination during influenza virus replication, although the molecular interactions underlying its potential impact on the coronaviruses including SARS-CoV-2, SARS-CoV, and Middle East respiratory syndrome coronavirus (MERS-CoV) remain unclear. We performed in silico studies to elucidate detailed molecular interactions between favipiravir and the SARS-CoV-2, SARS-CoV, MERS-CoV, and influenza virus RNA-dependent RNA polymerases (RdRp). As a result, no interactions between favipiravir ribofuranosyl-5′-triphosphate (F-RTP), the active form of favipiravir, and the active sites of RdRps (PB1 proteins) from influenza A (H1N1)pdm09 virus were found, yet the agent bound to the tunnel of the replication genome of PB1 protein leading to the inhibition of replicated RNA passage. In contrast, F-RTP bound to the active sites of coronavirus RdRp in the presence of the agent and RdRp. Further, the agent bound to the replicated RNA terminus in the presence of agent, magnesium ions, nucleotide triphosphate, and RdRp proteins. These results suggest that favipiravir exhibits distinct mechanisms of action against influenza virus and various coronaviruses.

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Section: Introductionmentioning

confidence: 99%

Detailed Molecular Interactions of Favipiravir with SARS-CoV-2, SARS-CoV, MERS-CoV, and Influenza Virus Polymerases In Silico

et al. 2020

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“…Baloxavir was approved in February 2018 and became the most-used influenza antiviral in the 2018-19 season in Japan. We initiated nationwide monitoring of baloxavir susceptibility of influenza viruses and found that 2.3% (9/395) of A(H1N1)pdm09 and 8.0% (34/424) of A(H3N2) viruses possessed amino acid substitutions associated with reduced susceptibility to baloxavir in the polymerase acidic subunit (PA) during this season (2). We did not detect any influenza B viruses that were resistant to the NA inhibitors or baloxavir.…”

Section: Accepted Manuscript Textmentioning

confidence: 94%

Detection of a Peramivir-Resistant Influenza B/Yamagata-Lineage Virus Imported from Indonesia in Aichi, Japan, March 2019

et al. 2020

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“…Another point to be considered in CoV treatment is that RNA viruses are known to have high levels of mutations (error rate) in the replication process (Ganeshpurkar et al, 2019). This can result in resistance to antiviral treatment, as observed for HIV, HCV, and Influenza viruses (Laplante and St George, 2014;Li and Chung, 2019;Olearo et al, 2019;Takashita, 2020). A recent study in pre-print pointed to the genomic variability of SARS-CoV-2 and the intra-patient capacity of polymorphic quasispecies, which may offer resistance to antiviral drugs (Karamitros et al, 2020).…”

Section: Perspectivesmentioning

confidence: 99%

Antivirals Against Coronaviruses: Candidate Drugs for SARS-CoV-2 Treatment?

et al. 2020

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Coronaviruses (CoVs) are a group of viruses from the family Coronaviridae that can infect humans and animals, causing mild to severe diseases. The ongoing pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) represents a global threat, urging the development of new therapeutic strategies. Here we present a selection of relevant compounds that have been described from 2005 until now as having in vitro and/or in vivo antiviral activities against human and/or animal CoVs. We also present compounds that have reached clinical trials as well as further discussing the potentiality of other molecules for application in (re)emergent CoVs outbreaks. Finally, through rationalization of the data presented herein, we wish to encourage further research encompassing these compounds as potential SARS-CoV-2 drug candidates.

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Influenza Polymerase Inhibitors: Mechanisms of Action and Resistance

Cited by 46 publications

References 55 publications

Detailed Molecular Interactions of Favipiravir with SARS-CoV-2, SARS-CoV, MERS-CoV, and Influenza Virus Polymerases In Silico

Detailed Molecular Interactions of Favipiravir with SARS-CoV-2, SARS-CoV, MERS-CoV, and Influenza Virus Polymerases In Silico

Detection of a Peramivir-Resistant Influenza B/Yamagata-Lineage Virus Imported from Indonesia in Aichi, Japan, March 2019

Antivirals Against Coronaviruses: Candidate Drugs for SARS-CoV-2 Treatment?

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