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

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.