Civra Andrea, Costantino Matteo, Porporato Domiziana, Francese Rachele, Donalisio Manuela, Poli Giuseppe, Marinozzi Maura, Lembo David
Department of Clinical and Biological Sciences, University of Turin, Orbassano, Turin, 10043, Italy.
Department of Clinical and Biological Sciences, University of Turin, Orbassano, Turin, 10043, Italy; National PhD Programme in One Health Approaches to Infectious Diseases and Life Science Research, Department of Public Health, Experimental and Forensic Medicine, University of Pavia, Pavia, 27100, Italy.
Antiviral Res. 2025 Apr;236:106113. doi: 10.1016/j.antiviral.2025.106113. Epub 2025 Feb 13.
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 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.
水痘带状疱疹病毒（VZV）是一种属于疱疹病毒科的重要病原体。原发性VZV感染会引发水痘，并导致感觉神经节的潜伏感染。在生命后期，VZV可重新激活，引发带状疱疹（HZ），这在免疫功能低下的个体中可能与严重并发症相关。目前，用于治疗VZV感染的现有抗病毒药物靶向DNA复制阶段；然而，免疫功能低下和免疫功能正常的患者均已出现对这些药物的耐药性。因此，鉴定针对VZV感染的新型抗病毒分子是当务之急。最近，我们的研究小组证明，内源性氧化甾醇25R,26 - 羟基胆固醇（25R,26OHC，更常用的名称为27 - 羟基胆固醇）和一种名为PFM067的氧化甾醇合成类似物可抑制单纯疱疹病毒（HSV）复制。在本研究中，我们探讨了25 - 羟基胆固醇（25OHC）、25R,26OHC和PFM067对VZV的抗病毒活性。我们证明，25R,26OHC和PFM067对VZV具有抗病毒活性，其半数有效浓度在低微摩尔范围内，并且能够显著减小病毒蚀斑的面积。此外，与我们小组对HSV - 2的研究结果类似，25R,26OHC和PFM067可抑制病毒糖蛋白gE从顺式高尔基体区室的释放。此外，我们还表明，25R,26OHC和PFM067与阿昔洛韦（ACV）联合使用时具有协同作用。25R,26OHC和PFM067具有令人期待的抗病毒活性，并且与ACV相比其作用机制不同，这使得这些分子成为进一步研究氧化甾醇分子靶点的合适候选物。
