Oral Antiviral Prodrugs for Biodefense Initiative

生物防御计划的口服抗病毒前药

• 批准号: 6818575
• 负责人: John M Hilfinger
• 金额: $ 106.11万
• 依托单位: TSRL, INC.
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-02-01 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6818575
• 关键词: Poxviridae; analog; antiviral agents; bioinformatics; bioterrorism /chemical warfare; carboxylic ester hydrolases; cell line; chemical stability; cidofovir; cooperative study; drug design /synthesis /production; enzyme activity; foscarnet; gastrointestinal drug absorption; human genetic material tag; laboratory rat; microarray technology; oral administration; pharmacokinetics; prodrugs; proteomics; solubility; thiosemicarbazones; toxicology; vaccinia virus

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.

描述（由申请人提供）：该项目涉及针对NIAID类别A，B＆C优先病原体的多种抗病毒化合物的合成和测试。已证明母体化合物具有抗病毒特性，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对于口服递送的适用性，将测试化合物的生物药物特性1）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理。为了确定目标组织中化合物（或前药的“激活”）的代谢，将筛选化合物在多种组织匀浆中的稳定性，包括肠道和肝匀浆，病毒感染的细胞匀浆和纯化的活化酶（例如，BPHL）。为了确定化合物的活性，将筛选它们在组织培养模型中针对各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论，将在病毒感染的细胞系统中评估前药化合物的作用，并与观察到的活性和相关转运蛋白和潜在激活酶的活性和表达水平相关。最后，将对此筛查过程产生的主要候选人进行大鼠的生物利用度测试。 初始毒理学测试（14天）将在显示出良好生物利用度的潜在客户上进行。