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 {(R)-N-(1-(3,4′-difluoro-[1,1′-biphenyl]-4-yl)-2-(1H-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.

中文翻译：

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临床批准的抗真菌药泊沙康唑可抑制人类巨细胞病毒复制。

泊沙康唑（PCZ）是一种临床批准的药物，主要用于真菌感染的预防和挽救疗法。在这里，我们报告其先前未描述的抗人巨细胞病毒（HCMV）活性。通过使用抗病毒测定，我们证明了PCZ以及其他氮杂类抗真菌剂具有广泛的抗HCMV活性，可针对不同的菌株（包括低通过次数的临床分离株和抗病毒DNA聚合酶抑制剂的菌株）具有活性。使用药理学方法，我们确定了对人细胞色素P450 51（hCYP51）或羊毛甾醇14α脱甲基酶（泊沙康唑在感染细胞中的细胞靶标）的抑制作用是该药物抗HCMV活性的机制。确实，HCMV感染会刺激hCYP51的表达，而羊毛甾醇类似物VFV会抑制其酶促活性{R）-N-（1-（3,4'-二氟-[1,1'-联苯] -4-基）-2-（1 H-咪唑-1-基）乙基）-4-（5-苯基-1,3,4-恶二唑-2-基）苯甲酰胺}或PCZ降低HCMV产量和释放病毒颗粒的传染性。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，而更昔洛韦（GCV）和PCZ在抑制HCMV复制中起协同作用。综上所述，这些发现表明，这种临床上认可的药物作为具有双重抗菌作用的候选抗HCMV药物，在宿主导向的抗病毒策略的开发中值得进一步研究。