Department of Molecular Medicine, University of Padua, Padua, Italy
Department of Life Sciences and Systems Biology, University of Turin, Turin, Italy.
Antimicrob Agents Chemother. 2020 Sep 21;64(10). doi: 10.1128/AAC.00056-20.
Posaconazole (PCZ) is a clinically approved drug used predominantly for prophylaxis and salvage therapy of fungal infections. Here, we report its previously undescribed anti-human cytomegalovirus (HCMV) activity. By using antiviral assays, we demonstrated that PCZ, along with other azolic antifungals, has a broad anti-HCMV activity, being active against different strains, including low-passage-number clinical isolates and strains resistant to viral DNA polymerase inhibitors. Using a pharmacological approach, we identified the inhibition of human cytochrome P450 51 (hCYP51), or lanosterol 14α demethylase, a cellular target of posaconazole in infected cells, as a mechanism of anti-HCMV activity of the drug. Indeed, hCYP51 expression was stimulated upon HCMV infection, and the inhibition of its enzymatic activity by either the lanosterol analog VFV {()--(1-(3,4'-difluoro-[1,1'-biphenyl]-4-yl)-2-(1-imidazol-1-yl)ethyl)-4-(5-phenyl-1,3,4-oxadiazol-2-yl)benzamide} or PCZ decreased HCMV yield and infectivity of released virus particles. Importantly, we observed that the activity of the first-line anti-HCMV drug ganciclovir was boosted tenfold by PCZ and that ganciclovir (GCV) and PCZ act synergistically in inhibiting HCMV replication. Taken together, these findings suggest that this clinically approved drug deserves further investigation in the development of host-directed antiviral strategies as a candidate anti-HCMV drug with a dual antimicrobial effect.
泊沙康唑（PCZ）是一种已临床批准的药物，主要用于预防和挽救真菌感染。在这里，我们报告了其以前未描述的抗人巨细胞病毒（HCMV）活性。通过使用抗病毒测定法，我们证明 PCZ 与其他唑类抗真菌药一样，具有广泛的抗 HCMV 活性，可有效对抗包括低传代数临床分离株和对病毒 DNA 聚合酶抑制剂耐药的株在内的不同株。通过药理学方法，我们确定了抑制人细胞色素 P450 51（hCYP51）或羊毛甾醇 14α 脱甲基酶，即 PCZ 在受感染细胞中的细胞靶标，是该药物抗 HCMV 活性的机制。实际上，HCMV 感染后 hCYP51 的表达受到刺激，并且通过羊毛甾醇类似物 VFV（()--(1-(3,4'-二氟-[1,1'-联苯]-4-基)-2-(1-咪唑-1-基)乙基)-4-(5-苯基-1,3,4-恶二唑-2-基)苯甲酰胺）或 PCZ 抑制其酶活性会降低 HCMV 产量和释放病毒颗粒的感染性。重要的是，我们观察到一线抗 HCMV 药物更昔洛韦的活性被 PCZ 增强了十倍，并且更昔洛韦（GCV）和 PCZ 协同作用抑制 HCMV 复制。综上所述，这些发现表明，这种已临床批准的药物值得进一步研究，以开发具有双重抗菌作用的宿主定向抗病毒策略作为候选抗 HCMV 药物。
