Small Molecule Inhibitors Targeting Adenovirus

项目总结 腺病毒(Ad)感染对免疫功能低下的儿童患者是一个重大的健康风险，并可导致 严重并发症，如肺炎、尿路感染和肝炎。腺病毒在军队中流行 招募在基础训练设施工作的人群，在那里他们被牵连到复发 发热性呼吸道疾病的暴发。一种有效对抗4型和7型Ad血清型的疫苗已获得批准 FDA，但这种疫苗的长期可获得性尚不清楚，而且不能对 预防其他对健康构成严重威胁的Ad血清型感染，包括6型和 14已导致青少年和成人患者患上致命的呼吸系统疾病。西多福韦(CDV、HPMPC)、 无环核苷膦(ANP)衍生物，被FDA批准用于治疗CMV视网膜炎。 虽然没有被FDA批准用于治疗Ad感染，但它在临床上经常使用。CDV有 由于其渗透性有限，细胞抗Ad效力相对适中，必须静脉给药 由于其口服生物利用度较低。CDV的另一个局限性是其肾脏毒性，因为它在肾脏中浓缩。 组织。最近，CDV和HPMPA的某些“可调”前药在该大学合成。南加州 (USC)已被证明在体外对四种Ad血清型的效力要强几个数量级 在叙利亚仓鼠模型上对Ad6有口服效果。拟议的研究将高度建立在这些基础上 有希望的初步数据来阐明这些活性前体药物的SAR和机制以及结构上的相关 衍生品。将合成一系列具有不同结构特征的前药类似物 并与六种强毒的Ad血清型进行了抗Ad活性比较。类比还将在稳定性方面进行比较 PK的特征、在仓鼠模型中的毒性以及最有希望的前药将被进一步评估 在叙利亚仓鼠模型中对抗Ad6的有效性。这项研究将由一名 由查尔斯·麦肯纳教授(南加州大学模拟设计与合成)、马克·普里查德教授领导的跨学科团队 (大学)阿拉巴马-伯明翰大学教授威廉·沃尔德(圣路易斯大学，体内研究)， 的最终目标是确定和开发一种安全、高效的CDV口服前药用于治疗 急性呼吸道疾病和在免疫受损的个人中传播感染。

PROJECT SUMMARY Adenovirus (Ad) infection is a significant health risk for immune-compromised pediatric patients, and can lead to serious complications such as pneumonia, urinary infections and hepatitis. Adenoviruses are endemic in military recruit populations engaging in basic training installations where they have been implicated in recurring outbreaks of febrile respiratory disease. A vaccine effective against Ad serotypes 4 and 7 has been licensed by the FDA, but the long-term availability of this vaccine is unclear, and immunization is not available for the prevention of infections by other Ad serotypes presenting a serious threat to health, including serotypes 6 and 14 which have caused fatal respiratory disease in both juvenile and adult patients. Cidofovir (CDV, HPMPC), an acyclic nucleoside phosphonate (ANP) derivative, is approved by the FDA for treatment of CMV retinitis. Although not approved by the FDA for treatment of Ad infection, it is used frequently in the clinic. CDV has relatively modest cellular anti-Ad potency due to its limited permeability and must be administered intravenously due to its low oral bioavailability. A further limitation of CDV is its renal toxicity due to concentration in kidney tissue. Recently, certain “tunable” prodrugs of CDV and HPMPA synthesized at the Univ. of Southern California (USC) have been demonstrated to be several orders of magnitude more potent against four Ad serotypes in vitro and orally effective against Ad6 in a Syrian hamster model. The proposed research will build on these highly promising preliminary data to elucidate the SAR and mechanism of these active prodrugs and structurally related derivatives. A series of prodrug analogs will be synthesized having variable structural features in the promoiety and evaluated for anti-Ad activity vs six virulent Ad serotypes. The analogs will also be compared for stability and PK characteristics, toxicity in a hamster model, and the most promising prodrugs will be further evaluated for efficacy against Ad6 in the Syrian hamster model. This research, which will be performed by an interdisciplinary team led by Prof. Charles McKenna (USC, analog design and synthesis), Prof. Mark Prichard (Univ. of Alabama-Birmingham, in vitro studies) and Prof. William Wold (Saint Louis University, in vivo studies), has the ultimate goal of identifying and developing a safe, highly effective oral prodrug of CDV for the treatment of acute respiratory disease and disseminating infection in immune-compromised individuals.