Oral Antiviral Prodrugs for Biodefense Initiative

生物防御计划的口服抗病毒前药

• 批准号: 7356460
• 负责人: John M Hilfinger
• 金额: $ 108.62万
• 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/7356460
• 关键词: Animal Testing; Antiviral Agents; Area; BPHL gene; Bioinformatics; Biological Availability; Biological Products; Buffers; California; Categories; Cells; Characteristics; Cidofovir; Class; Cleaved cell; Clinical; Clinical Trials; Collaborations; Cowpox virus; Cyclopropanes; DNA; Development; Diagnostic; Dipeptides; Disease; Drug toxicity; Enzyme Activation; Enzymes; Evaluation; Event; Gene Chips; Goals; Human; Human Cell Line; Hydrolysis; Immunologic Adjuvants; Intestines; Lead; Liver; Mediating; Metabolism; Methodology; Michigan; Modeling; National Institute of Allergy and Infectious Disease; Nucleoside Transporter; Numbers; Oral; Outcome; Parents; Permeability; Pharmaceutical Preparations; Pharmacologic Substance; Plasma; Plasma Cells; Process; Prodrugs; Property; Proteomics; RNA Viruses; Rattus; Research; Sampling; Screening procedure; Smallpox; Solubility; Stomach; System; Targeted Research; Techniques; Testing; Therapeutic Agents; Thiosemicarbazones; Tissues; Toxicology; Universities; Vaccine Adjuvant; Vaccinia; Valganciclovir; Viral; Viral Physiology; Virus; Virus Diseases; Work; absorption; adefovir dipivoxil; analog; base; biodefense; biphenyl hydrolase-related protein; carbene; compliance behavior; cost; cyclopropane; cytotoxicity; day; design; improved; interest; novel; nucleoside analog; pathogen; research and development; success; targeted delivery; tenofovir disoproxil; therapeutic vaccine; tissue culture; uptake; valacyclovir

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 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，我们建议合成多种母体化合物的类似物，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，我们将测试这些化合物的生物制药特性：1)在胃和肠道缓冲液中的溶解度和稳定性