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Virus research2020; 278; 197867; doi: 10.1016/j.virusres.2020.197867

Structural insights into NS5B protein of novel equine hepaciviruses and pegiviruses complexed with polymerase inhibitors.

Abstract: Infections produced by hepaciviruses have been associated with liver disease in horses. Currently, at least three viruses belonging to the Flaviviridae family are capable of producing a chronic infection in equines: non-primate hepacivirus (NPHV), Theiler's disease-associated virus (TDAV), and equine pegivirus (EPgV). The RNA-dependent RNA polymerases of viruses (RdRp) (NS5 protein), from the flavivirus family, use de novo RNA synthesis to initiate synthesis. The two antiviral drugs currently used to treat hepatitis C (HCV), sofosbuvir and dasabuvir, act on the viral NS5B polymerase as nucleoside and non-nucleoside inhibitors, respectively. Both drugs have shown significant clinical inhibition of viral response. In this work, we aimed to model the NS5B polymerase of the equine hepacivirus (EHCV) subtypes 1 and 2, TDAV and EPgV, to assess whether current direct-acting antiviral drugs against HCV interact with these proteins. Crystal structures of HCV-NS5B were used as templates for modeling target sequences in both conformations (open and closed). Also, molecular docking of sofosbuvir and dasabuvir were performed to predict their possible binding modes at the modeled NS5B polymerase binding sites. We observed that the NS5B models of the EHCV and EPgV shared well-conserved 3D structures to HCV-NS5B and other RdRps, suggesting functional conservation. Interactions of EHCV subtypes 1, 2 and TDAV polymerases with sofosbuvir showed a similar molecular interaction pattern compared to HCV-NS5B, while interactions with dasabuvir were less conserved. In silico studies of molecular interactions between these modeled structures and sofosbuvir suggest that this compound could be efficient in combating equine pathogens, thus contributing to animal welfare.
Copyright © 2020 Elsevier B.V. All rights reserved.
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Publication Date: 2020-01-20 PubMed ID: 31972246DOI: 10.1016/j.virusres.2020.197867Google Scholar: Lookup
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  • Comparative Study
  • Journal Article
  • Research Support
  • Non-U.S. Gov't

Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

The research is focused on the analysis of NS5B protein structure of equine hepaciviruses and pegiviruses, and its interaction with polymerase inhibitors specifically used in hepatitis C treatment. The overview entails the modeling of this protein and investigating how two antiviral drugs, sofosbuvir and dasabuvir, interact with these models.

Objective and Background

  • The study aims to understand the interaction of direct-acting antiviral drugs—sofosbuvir and dasabuvir—with the NS5B protein (an RNA-dependent RNA polymerase) of equine hepaciviruses and pegiviruses.
  • These viruses belong to the Flaviviridae family and have been linked to chronic liver disease in horses.
  • The antiviral drugs sofosbuvir and dasabuvir have been successfully used in the treatment of hepatitis C, acting as nucleoside and non-nucleoside inhibitors on the viral NS5B polymerase.

Methods

  • The researchers modeled the NS5B polymerase of the equine hepacivirus (EHCV) subtypes 1 and 2, Theiler’s disease-associated virus (TDAV), and equine pegivirus (EPgV).
  • The modeling process used crystal structures of HCV-NS5B as templates to produce target sequences in both open and closed conformations.
  • They then performed molecular docking of sofosbuvir and dasabuvir to predict their possible binding modes at the modeled NS5B polymerase binding sites.

Results

  • The NS5B models of the EHCV and EPgV were found to share well-conserved 3D structures with HCV-NS5B and other RdRps, suggesting functional conservation.
  • Interaction patterns of EHCV subtypes 1 and 2 and TDAV polymerases with sofosbuvir were similar to those of HCV-NS5B, but these patterns were less conserved with dasabuvir.
  • The in silico studies of molecular interactions suggest that sofosbuvir could potentially be effective against equine pathogens, which could contribute to improving animal welfare.

Implications

  • This study provides valuable insights on the potential use of antiviral drugs, particularly sofosbuvir, in treating equine viral diseases.
  • The research might also foster the development of new drugs for veterinary use, particularly against pathogens that cause chronic infection in equines.

Cite This Article

APA
de Albuquerque PPLF, Santos LHS, Antunes D, Caffarena ER, Figueiredo AS. (2020). Structural insights into NS5B protein of novel equine hepaciviruses and pegiviruses complexed with polymerase inhibitors. Virus Res, 278, 197867. https://doi.org/10.1016/j.virusres.2020.197867

Publication

Virus research
ISSN: 1872-7492
NlmUniqueID: 8410979
Country: Netherlands
Language: English
Volume: 278
Pages: 197867

Researcher Affiliations

de Albuquerque, Pedro Pereira Lira Furtado
  • Laboratório de Desenvolvimento Tecnológico em Virologia, Instituto Oswaldo Cruz, Fiocruz, Rio de Janeiro, Brazil.
Santos, Lucianna H S
  • Laboratório de Modelagem Molecular e Planejamento de Fármacos, Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
Antunes, Deborah
  • Laboratório de Genômica Funcional e Bioinformática, Instituto Oswaldo Cruz, Fiocruz, Rio de Janeiro, Brazil. Electronic address: deborah.santos@fiocruz.br.
Caffarena, Ernesto Raul
  • Grupo de Biofísica Computacional e Modelagem Molecular, Programa de Computação Científica, Fiocruz, Rio de Janeiro, Brazil.
Figueiredo, Andreza Soriano
  • Laboratório de Desenvolvimento Tecnológico em Virologia, Instituto Oswaldo Cruz, Fiocruz, Rio de Janeiro, Brazil.

MeSH Terms

  • Animals
  • Antiviral Agents / chemistry
  • Antiviral Agents / pharmacology
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Hepacivirus / chemistry
  • Hepacivirus / drug effects
  • Horses / virology
  • Molecular Docking Simulation
  • Pegivirus / chemistry
  • Pegivirus / drug effects
  • Sequence Alignment
  • Viral Nonstructural Proteins / chemistry

Conflict of Interest Statement

Declaration of Competing Interest The authors declare no competing interests.

Citations

This article has been cited 8 times.
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