Human adenoviruses (AdV) cause generally mild infections of the respiratory and GI tracts as well as some other tissues. However, AdV can cause serious infection in severely immunosuppressed individuals, especially pediatric patients undergoing allogeneic hematopoietic stem cell transplantation, where mortality rates are up to 80% with disseminated disease. Despite the seriousness of AdV disease, there are no drugs approved specifically to treat AdV infections. We report here that USC-087, an N-alkyl tyrosinamide phosphonate ester prodrug of HPMPA, the adenine analog of cidofovir, is highly effective against multiple AdV types in cell culture. USC-087 is also effective against AdV-C6 in our immunosuppressed permissive Syrian hamster model. In this model, hamsters are immunosuppressed by treatment with high dose cyclophosphamide. Injection of AdV-C6 (or AdV-C5) intravenously leads to a disseminated infection that resembles the disease seen in humans, including death. We have tested the efficacy of orally-administered USC-087 against the median lethal dose of intravenously administered AdV-C6. USC-087 completely prevented or significantly decreased mortality when administered up to 4 days post challenge. USC-087 also prevented or significantly decreased liver damage caused by AdV-C6 infection, and suppressed virus replication even when administered 4 days post challenge. These results imply that USC-087 is a promising candidate for drug development against HAdV infections.

人腺病毒（AdV）通常引起呼吸道和胃肠道以及其他一些组织的轻度感染。但是，AdV会在受到严重免疫抑制的个体中引起严重感染，尤其是接受同种异体造血干细胞移植的儿科患者，其中散播性疾病的死亡率高达80％。尽管AdV疾病很严重，但尚无专门批准用于治疗AdV感染的药物。我们在这里报告USC-087，NHPMPA的β-烷基酪氨酸酰胺膦酸酯前药，西多福韦的腺嘌呤类似物，在细胞培养中对多种AdV类型具有很高的抵抗力。在我们的免疫抑制性宽松叙利亚仓鼠模型中，USC-087对AdV-C6也有效。在该模型中，仓鼠通过用大剂量环磷酰胺治疗而被免疫抑制。静脉内注射AdV-C6（或AdV-C5）会导致传播性感染，这种感染类似于人类所见的疾病，包括死亡。我们已经测试了口服USC-087对静脉内施用的AdV-C6的中值致死剂量的功效。当攻击后长达4天给药时，USC-087可以完全预防或显着降低死亡率。USC-087还预防或显着降低了AdV-C6感染引起的肝损害，甚至在攻击后4天给药也能抑制病毒复制。这些结果表明，USC-087是抗HAdV感染药物开发的有希望的候选者。