HRC-derived peptide potently blocks Peste des petits ruminants virus entry by inhibiting F protein fusion.
Background
Peste des petits ruminants virus (PPRV) is a highly contagious morbillivirus devastating small ruminant populations, posing a significant threat to global food security and ongoing eradication efforts. Despite effective vaccines, a critical gap exists in antiviral therapeutics for outbreak control. This research addresses the need for novel interventions by targeting the viral fusion machinery, specifically the PPRV fusion (F) protein, which is essential for viral entry into host cells. Inhibiting this mechanism could provide a crucial tool to complement vaccination strategies.
Study Design
Researchers designed and characterized a synthetic HRC peptide derived from the heptad repeat C region of the PPRV fusion (F) protein. Its antiviral activity was assessed in vitro using several models: PPRV F/H-mediated membrane fusion assays, a vesicular stomatitis virus (VSV)-based pseudovirus system, and a replicative morbillivirus model (canine distemper virus). The peptide's ability to inhibit fusion was measured dose-dependently, and its synergistic potential was evaluated in combination with a fusion inhibitory compound (FIP). Biophysical analyses, including α-helical propensity and serum stability, alongside molecular docking and dynamics simulations, elucidated its mechanism of action.
Results
The HRC peptide potently inhibited PPRV F/H-mediated membrane fusion in a dose-dependent manner. It demonstrated an IC₅₀ of 11.80 μM for SLAM/CD150-dependent entry and 18.11 μM for nectin-4-dependent entry. > Consistently, the peptide blocked viral entry in a VSV-based pseudovirus system with an IC₅₀ of 14.5 μM. Antiviral activity was further confirmed in a replicative morbillivirus model (canine distemper virus), showing significant inhibition in both co-treatment and virus pre-treatment conditions. Notably, combining the HRC peptide with a fusion inhibitory compound (FIP) resulted in synergistic antiviral activity, with a Fractional Inhibitory Concentration Index (FICI) of 0.44. Biophysical studies revealed strong α-helical propensity in membrane-mimetic environments and high stability in human serum. Molecular simulations indicated the peptide stabilizes the F protein by bridging critical domains via a persistent hydrogen-bond network, preventing conformational changes needed for membrane fusion.
Key Findings
- HRC-derived peptide potently inhibited PPRV F/H-mediated membrane fusion.
- IC₅₀ values were 11.80 μM for
SLAM/CD150-dependent and 18.11 μM fornectin-4-dependent entry. - Blocked viral entry in a
VSV-based pseudovirus system with an IC₅₀ of 14.5 μM. - Showed synergistic antiviral activity (FICI = 0.44) when combined with a fusion inhibitory compound.
- Stabilizes the
F proteinvia a hydrogen-bond network, preventing membrane fusion.
Why It Matters
This research provides the first evidence that HRC-derived peptides can effectively inhibit PPRV entry, offering a promising new class of antiviral agents. For clinicians and public health officials, this represents a crucial step towards developing therapeutics to manage outbreaks, especially where vaccination alone is insufficient or during early stages of an outbreak. The synergistic activity with FIPs suggests that combination therapies could be highly effective, potentially allowing for lower individual doses and reduced resistance risk. This finding opens the door for developing targeted antiviral strategies that complement existing vaccines, enhancing global efforts to eradicate PPRV and protect small ruminant livestock. While currently in vitro, this work lays the groundwork for future in vivo studies and potential clinical translation, moving towards a usable protocol for disease control.
hrc-peptide
pprv
antiviral
fusion-inhibitor
morbillivirus
in-vitro