# In Silico Characterization of Two Human Pegivirus Proteins Highlights Similarities with Hepatitis C Virus and Possible Therapeutic Repurposing

## TL;DR

This study uses computer modeling to compare two proteins from Human Pegivirus with similar proteins in Hepatitis C Virus, suggesting existing Hepatitis C drugs might work against Human Pegivirus.

## Contribution

The study provides structural insights into HPgV proteins and suggests therapeutic repurposing of HCV antivirals.

## Key findings

- HPgV NS3 and NS5B proteins show minimal structural differences compared to HCV proteins.
- FDA-approved HCV drugs showed potential binding to conserved residues in HPgV proteins.
- Docking scores indicate possible repurposing of HCV antivirals for HPgV treatment.

## Abstract

Human Pegivirus (HPgV) is an understudied flavivirus that is highly prevalent and often persists in the blood and tissues of humans. HPgV-infected brain tissue from individuals with Parkinson’s disease has shown significant transcriptomic and immune signaling differences compared to non-infected Parkinson’s brains. The HPgV genome is similar to Hepatitis C Virus (HCV), a well-characterized flavivirus with multiple approved small-molecule therapeutics. Here, we used HCV crystal structures to create homology models for two HPgV non-structural (NS) proteins, the serine protease (NS3) and the RNA-dependent RNA polymerase (NS5B), and performed molecular dynamic simulations. HCV and HPgV proteins had minimal structural differences, as seen by the Root Mean Square Deviation (RMSD) difference between NS3 (1.00 Å) and NS5B (1.26 Å). FDA-approved small molecules were then docked in silico to the NS3 and NS5B subunits of HCV and HPgV. HCV had weak to moderate correlated docking scores with HPgV NS3 (R2 = 0.21, p < 0.001) and NS5B (R2 = 0.58, p < 0.001). The predicted protein–ligand interactions showed potential binding between HCV antivirals and conserved residues of HPgV, including the catalytic triad for NS3 or the GDD motif for NS5B. Together, these results provide structural insights for key HPgV proteins and highlight possibilities for therapeutic repurposing of HCV antivirals.