Small Molecule Inhibitors Targeting Adenovirus

项目摘要 腺病毒（Ad）感染是免疫受损儿科患者的重大健康风险，并可导致 严重并发症，如肺炎、尿路感染和肝炎。腺病毒是军队中的地方病 招募从事基本训练设施的人员，他们参与了经常性的 发热性呼吸道疾病的爆发。有效对抗Ad血清型4和7的疫苗已被许可由 FDA，但这种疫苗的长期可用性尚不清楚，免疫接种不适用于 预防严重威胁健康的其他Ad血清型的感染，包括血清型6和 14种在青少年和成人患者中引起致命的呼吸道疾病。西多福韦（CDV，HPMPC）， 无环核苷膦酸酯（ANP）衍生物，被FDA批准用于治疗CMV视网膜炎。 虽然FDA尚未批准用于治疗Ad感染，但它在临床上经常使用。CDV有 由于其有限的渗透性， 由于其口服生物利用度低。CDV的另一个局限性是由于在肾脏中的浓度而引起的肾毒性 组织.最近，在南加州大学合成了CDV和HPMPA的某些“可调”前药 (USC)已经证明在体外对四种Ad血清型的效力高出几个数量级 并且在叙利亚仓鼠模型中口服有效对抗Ad6。拟议的研究将建立在这些高度 有希望的初步数据，以阐明这些活性前药和结构相关的SAR和机制， 衍生物.将合成一系列前体药物类似物，其在前体部分具有可变的结构特征 并评价抗Ad活性与六种毒性Ad血清型的对比。还将比较类似物的稳定性 和PK特征，仓鼠模型中的毒性，以及最有前途的前药将进一步评估 在叙利亚仓鼠模型中针对Ad6的功效。这项研究将由一名 由Charles McKenna教授（南加州大学，模拟设计与合成）、Mark Prichard教授 （伯明翰大学，体外研究）和William Wold教授（圣刘易斯大学，体内研究）， 最终目的是鉴定和开发一种安全、高效的CDV口服前药， 急性呼吸道疾病和传播性感染的免疫功能低下的个人。

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.