The critical consequences of human cytomegalovirus (HCMV) infection in the transplant population and in congenitally infected infants, the limited treatment options for HCMV, and the rise of resistant mutants toward existing therapies has fueled the search for new anti-HCMV agents. A pp28-luciferase recombinant HCMV was used as a reporter system for high-throughput screening of HCMV inhibitors. Approximately 400 000 compounds from existing libraries were screened. Subsequent validation assays using resynthesized compounds, several virus strains, and detailed virology assays resulted in the identification of five structurally unique and selective HCMV inhibitors, active at sub to low micromolar concentrations. Further characterization revealed that each compound inhibited a specific stage of HCMV replication. One compound was also active against herpes simplex virus (HSV1 and HSV2), and another compound was active against Epstein-Barr virus (EBV). Drug combination studies revealed that all five compounds were additive with ganciclovir or letermovir. Future studies will focus on optimization of these new anti-HCMV compounds along with mechanistic studies.

中文翻译：

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五种不同的新型人类巨细胞病毒抑制剂的验证和表征。

人类巨细胞病毒 (HCMV) 感染对移植人群和先天性感染婴儿的严重后果、HCMV 治疗选择的有限以及对现有疗法耐药突变体的增加，推动了对新抗 HCMV 药物的寻找。pp28-荧光素酶重组 HCMV 用作报告系统，用于高通量筛选 HCMV 抑制剂。从现有库中筛选了大约 400 000 种化合物。随后使用重新合成的化合物、几种病毒株和详细的病毒学测定进行的验证测定导致鉴定出五种结构独特且选择性的 HCMV 抑制剂，它们在亚至低微摩尔浓度下具有活性。进一步的表征表明，每种化合物都抑制 HCMV 复制的特定阶段。一种化合物还具有抗单纯疱疹病毒（HSV1 和 HSV2）的活性，另一种化合物具有抗 Epstein-Barr 病毒（EBV）的活性。药物组合研究表明，所有五种化合物均与更昔洛韦或莱特莫韦相加。未来的研究将集中于这些新的抗 HCMV 化合物的优化以及机制研究。