25R,26-hydroxycholesterol and an oxysterol synthetic analog inhibit Varicella zoster Virus replication
Andrea Civra1, Matteo Costantino1, Domiziana Porporato2
1Department of Clinical and Biological Sciences, University of Turin, Orbassano, Turin, 10043, Italy.
Antiviral Research
|February 15, 2025
Summary
New oxysterols, 25R,26-hydroxycholesterol and PFM067, show antiviral activity against Varicella-zoster Virus (VZV). These compounds, effective against VZV plaques and glycoprotein gE egress, also synergize with acyclovir.
Area of Science:
- Virology
- Molecular Biology
- Drug Discovery
Background:
- Varicella-zoster Virus (VZV) causes chickenpox and shingles, with reactivation posing risks, especially in immunocompromised individuals.
- Current antivirals target VZV DNA replication but face resistance issues, necessitating novel therapeutic strategies.
- Oxysterols, including 27-hydroxycholesterol (25R,26OHC) and synthetic analog PFM067, have shown prior efficacy against herpes simplex virus (HSV).
Purpose of the Study:
- To evaluate the antiviral potential of 25-hydroxycholesterol (25OHC), 25R,26OHC, and PFM067 against VZV.
- To investigate the mechanism of action of these oxysterols in VZV-infected cells.
- To assess the synergistic effects of oxysterols with existing VZV treatments like acyclovir.
Main Methods:
- In vitro antiviral assays to determine efficacy (EC50) and plaque reduction against VZV.
- Analysis of viral glycoprotein gE egress from the cis-Golgi compartment.
- Combination studies with acyclovir (ACV) to evaluate synergistic antiviral effects.
Main Results:
- 25R,26OHC and PFM067 demonstrated antiviral activity against VZV with low micromolar EC50 values.
- These oxysterols significantly reduced VZV plaque formation.
- 25R,26OHC and PFM067 were found to inhibit VZV glycoprotein gE egress from the cis-Golgi and synergize with acyclovir.
Conclusions:
- 25R,26OHC and PFM067 exhibit promising antiviral activity against VZV.
- Their distinct mechanism of action, inhibiting viral egress, offers a new therapeutic avenue.
- These oxysterols are potential candidates for further development as VZV therapeutics, particularly in combination therapies.
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