Oral Antiviral Prodrugs for Biodefense Initiative

描述（由申请人提供）：该项目涉及针对 NIAID A、B 和 C 类优先病原体的多种抗病毒化合物的合成和测试。母体化合物已被证明具有抗病毒特性，我们建议合成母体化合物的各种类似物，以优化其抗病毒活性和药物特性。为了确定这些化合物是否适合口服给药，将测试化合物的生物制药特性：1) 在胃和肠缓冲液中的溶解度和稳定性，以及 2）肠道通透性。此外，将进行运输研究以确定肠道摄取的机制。为了确定靶组织中化合物的代谢（或前药的“激活”），将筛选化合物在各种组织匀浆中的稳定性，包括肠和肝匀浆、病毒感染的细胞匀浆和纯化的激活酶（例如 BPHL）。为了确定这些化合物的活性，将在组织培养模型中筛选它们针对多种病毒靶标的抗病毒活性。使用基因芯片分析和蛋白质组学方法，将在病毒感染的细胞系统中评估前药化合物的作用，并将其与观察到的相关转运蛋白和潜在激活酶的活性和表达水平相关联。最后，将从该筛选过程中产生的主要候选药物将在大鼠中进行生物利用度测试。 将对显示良好生物利用度的先导物进行初步毒理学测试（14 天）。

DESCRIPTION (provided by applicant): The project involves the synthesis and testing of a variety of antiviral compounds that are directed against NIAID Category A, B & C Priority Pathogens. The parent compounds have been shown to have antiviral properties and we propose to synthesize a variety of analogs of the parent compounds in order to optimize their antiviral activities and pharmaceutical properties. To determine the suitability of these compounds for oral delivery, compounds will be tested for the biopharmaceutical properties of 1) solubility and stability in gastric and intestinal buffers and 2) intestinal permeability. Further, transport studies will be performed to determine the mechanism of intestinal uptake. To determine the metabolism of compounds (or "activation" in the case of prodrugs) in the target tissue, compounds will be screened for stability in a variety of tissue homogenates including intestinal and liver homogenates, virally-infected cell homogenates, and purified activation enzymes (e.g., BPHL). To determine the activity of the compounds, they will be screened for anti-viral activity against a variety of viral targets in tissue culture models. Using gene chip analysis and proteomic methodologies, the effect of the prodrug compounds will be evaluated in virally-infected cell based systems and correlated with the observed activities and expression levels of relevant transporters and potential activation enzymes. Finally, lead candidates that arise from this screening process will be tested for bioavailability in rats. Initial toxicology testing (14 day) will be performed on leads showing good bioavailability.