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

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...

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Autores principales: Sada, Mitsuru, Saraya, Takeshi, Ishii, Haruyuki, Okayama, Kaori, Hayashi, Yuriko, Tsugawa, Takeshi, Nishina, Atsuyoshi, Murakami, Koichi, Kuroda, Makoto, Ryo, Akihide, Kimura, Hirokazu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7589801/
https://www.ncbi.nlm.nih.gov/pubmed/33092045
http://dx.doi.org/10.3390/microorganisms8101610
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author Sada, Mitsuru
Saraya, Takeshi
Ishii, Haruyuki
Okayama, Kaori
Hayashi, Yuriko
Tsugawa, Takeshi
Nishina, Atsuyoshi
Murakami, Koichi
Kuroda, Makoto
Ryo, Akihide
Kimura, Hirokazu
author_facet Sada, Mitsuru
Saraya, Takeshi
Ishii, Haruyuki
Okayama, Kaori
Hayashi, Yuriko
Tsugawa, Takeshi
Nishina, Atsuyoshi
Murakami, Koichi
Kuroda, Makoto
Ryo, Akihide
Kimura, Hirokazu
author_sort Sada, Mitsuru
collection PubMed
description 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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spelling pubmed-75898012020-10-29 Detailed Molecular Interactions of Favipiravir with SARS-CoV-2, SARS-CoV, MERS-CoV, and Influenza Virus Polymerases In Silico Sada, Mitsuru Saraya, Takeshi Ishii, Haruyuki Okayama, Kaori Hayashi, Yuriko Tsugawa, Takeshi Nishina, Atsuyoshi Murakami, Koichi Kuroda, Makoto Ryo, Akihide Kimura, Hirokazu Microorganisms Communication 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. MDPI 2020-10-20 /pmc/articles/PMC7589801/ /pubmed/33092045 http://dx.doi.org/10.3390/microorganisms8101610 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Communication
Sada, Mitsuru
Saraya, Takeshi
Ishii, Haruyuki
Okayama, Kaori
Hayashi, Yuriko
Tsugawa, Takeshi
Nishina, Atsuyoshi
Murakami, Koichi
Kuroda, Makoto
Ryo, Akihide
Kimura, Hirokazu
Detailed Molecular Interactions of Favipiravir with SARS-CoV-2, SARS-CoV, MERS-CoV, and Influenza Virus Polymerases In Silico
title Detailed Molecular Interactions of Favipiravir with SARS-CoV-2, SARS-CoV, MERS-CoV, and Influenza Virus Polymerases In Silico
title_full Detailed Molecular Interactions of Favipiravir with SARS-CoV-2, SARS-CoV, MERS-CoV, and Influenza Virus Polymerases In Silico
title_fullStr Detailed Molecular Interactions of Favipiravir with SARS-CoV-2, SARS-CoV, MERS-CoV, and Influenza Virus Polymerases In Silico
title_full_unstemmed Detailed Molecular Interactions of Favipiravir with SARS-CoV-2, SARS-CoV, MERS-CoV, and Influenza Virus Polymerases In Silico
title_short Detailed Molecular Interactions of Favipiravir with SARS-CoV-2, SARS-CoV, MERS-CoV, and Influenza Virus Polymerases In Silico
title_sort detailed molecular interactions of favipiravir with sars-cov-2, sars-cov, mers-cov, and influenza virus polymerases in silico
topic Communication
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7589801/
https://www.ncbi.nlm.nih.gov/pubmed/33092045
http://dx.doi.org/10.3390/microorganisms8101610
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