Work

25R,26-hydroxycholesterol and an oxysterol synthetic analog inhibit Varicella zoster Virus replication

Year: 2025

Type: article

Abstract: Varicella-zoster Virus (VZV) is a relevant pathogen belonging to the herpesviridiae family. Primary VZV infection causes chickenpox, and results in latent infection of sensory ganglia. Later in life, VZV can reactivate causing herpes zoster (HZ), which can be associated with severe complications in immunocompromised individuals. Currently, the available antivirals used to treat VZV infection target the DNA replication stage; however, resistance to these drugs has been reported in both immunocompromised and immunocompetent patients. For this reason, the identification of new antiviral molecules against VZV infection is a priority. Recently our research group demonstrated that the endogenous oxysterol 25R,26-hydroxycholesterol (25R,26OHC, more commonly named 27-hydroxycholesterol) and an oxysterol synthetic analog named PFM067 inhibit herpes simplex virus (HSV) replication. In this study we explored the antiviral activity of 25-hydroxycholesterol (25OHC), 25R,26OHC, and PFM067 against VZV. We demonstrated that 25R,26OHC and PFM067 exert antiviral activity against VZV with an EC 50 in the low micromolar range and are able to significantly reduce the area of the viral plaques. Moreover, 25R,26OHC and PFM067 can inhibit the egress of viral glycoprotein gE from the cis-Golgi compartment, similarly to what demonstrated by our group for HSV-2. Additionally, we show that 25R,26OHC and PFM067 act synergistically when used in combination with acyclovir (ACV). The promising antiviral activity of 25R,26OHC and PFM067, along with their different mechanism of action compared to ACV, makes these molecules suitable candidates for further investigation of the molecular target of oxysterols. • In this study, we tested the activity of two enzymatic oxysterols (namely 25R,26OHC and 25OHC) against VZV. • We showed that 25R,26OHC, but not 25OHC is endowed with antiviral activity against VZV. • PFM067, a synthetic oxysterol analog active against HSV, is also endowed with antiviral activity against VZV. • Both 25R,26OHC and PFM067 sequester VZV glycoproteins E in the cis-Golgi compartment. • Both 25R,26OHC and PFM067 act synergistically with ACV to block VZV replication.

Source: Antiviral Research

DOI: 10.1016/j.antiviral.2025.106113