Mechanistic Approaches to Inhibition of Emerging DNA Viruses

抑制新兴 DNA 病毒的机​​制方法

• 批准号: 9456556
• 负责人: CHARLES E MCKENNA
• 金额: $ 25.55万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-01 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9456556
• 关键词: Address; Affect; Alabama; Amino Acids; Anabolism; Antibodies; Antiviral Agents; Biological Assay; Biological Availability; Biology; Bromodeoxyuridine; California; Cell Culture Techniques; Cells; Cidofovir; Clinic; Clinical; Collaborations; Cytomegalovirus; Cytoplasm; DNA; DNA Viruses; Data; Detection; Development; Disease; Effectiveness; Esters; Evaluation; Exhibits; Family; Fibroblasts; Foscarnet; Future; Goals; HHV-6B; Health; Herpesviridae; Herpesvirus 1; Human; In Vitro; Individual; Infection; Intestines; Laboratories; Length; Liquid substance; Liver; Measures; Metabolic; Metabolism; Methods; Molecular; Molecular Probes; Molecular Structure; Nucleosides; Nucleotides; Oral; Orthopoxvirus; Parents; Pathogenicity; Permeability; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Phosphate Buffer; Phospholipase C; Phospholipids; Physiological; Plasma; Polyomavirus; Positioning Attribute; Prodrugs; Property; Public Health; Rattus; Research; Research Personnel; Research Project Grants; Series; Solubility; Stomach; Structure; Structure-Activity Relationship; Tissues; Translations; United States National Institutes of Health; Universities; Vaccinia virus; Variant; Viral; Virus; Virus Diseases; adenine analog; alkyl group; analog; anti-viral efficacy; aqueous; cytotoxicity; design; effective therapy; efficacy testing; gastricsin; improved; in vitro activity; indexing; innovation; insight; lipophilicity; nephrotoxicity; novel; novel therapeutics; pathogen; penis foreskin; phosphonate; professor; scaffold; tool; uptake; viral DNA

PROJECT SUMMARY The NIH has identified a group of infective viruses as “emerging” because they are a growing threat to public health. This high priority list includes several DNA viruses. Infections with DNA viruses result in significant disease, but few drugs have been approved for this class of pathogens. Cidofovir (CDV, HPMPC) is an acyclic nucleoside phosphonate (ANP) known to exhibit activity against a spectrum of DNA viruses. However, like other ANPs as a class, CDV has significant drawbacks, including inherent lack of oral bioavailability, relatively low potency and nephrotoxicity. Certain novel N-alkyl tyrosinamide prodrugs of CDV and its adenine analog HPMPA recently designed and synthesized by the PI, Professor Charles McKenna at the University of Southern California (USC) exhibit greatly enhanced in vitro potency against CMV and several other DNA viruses relative to the parent drugs and improved selectivity indices. An important virus-dependent variation in potency, selectivity and efficacy enhancement is observed, which has not been explained mechanistically. In this R21 project, these prodrugs and a series of analogs with modified promoiety structures designed to affect activation by phospholipase C will be evaluated for stability and permeability under physiological conditions and for activity against CMV, HSV1, VACV and two emerging DNA viruses: HHV-6B and BK virus. The research will focus on associating individual promoiety structural features with uptake into infected cells and release of drug into the cytoplasm for uptake into viral DNA for each virus, using novel 5-BrHPMPU prodrug derivatives as probes. This information, correlated with the stability, metabolism and in vitro antiviral efficacy data for the five viruses will provide important insights into the mechanism underlying the exceptional but varied potency of this new class of prodrugs with respect to the viruses investigated, while introducing an innovative molecular tool to determine drug promoiety effectiveness. It is also expected to identify new, highly potent compounds for future development into effective therapies for infections by these viruses.

项目概要 美国国立卫生研究院 (NIH) 已将一组传染性病毒确定为“新兴”病毒，因为它们对公众的威胁日益严重 健康。这个高优先级列表包括几种 DNA 病毒。 DNA 病毒感染会导致严重后果 疾病，但很少有药物被批准用于治疗此类病原体。西多福韦 (CDV, HPMPC) 是一种无环 已知核苷膦酸酯 (ANP) 对一系列 DNA 病毒具有活性。然而，像其他 ANPs 作为一类，CDV 具有显着的缺点，包括固有缺乏口服生物利用度、相对较低 效力和肾毒性。 CDV及其腺嘌呤类似物HPMPA的某些新型N-烷基酪氨酸酰胺前药 最近由 PI、南加州大学 Charles McKenna 教授设计和合成 (USC) 相对于亲本，对 CMV 和其他几种 DNA 病毒的体外效力显着增强 药物和改进的选择性指数。效力、选择性和功效的重要病毒依赖性变异 观察到增强，但尚未从机制上解释。在这个 R21 项目中，这些前药 以及一系列具有修饰的前体结构的类似物，旨在影响磷脂酶 C 的激活 评估生理条件下的稳定性和渗透性以及针对 CMV、HSV1、 VACV 和两种新兴 DNA 病毒：HHV-6B 和 BK 病毒。该研究将侧重于将个人 前体结构特征，被感染细胞摄取并将药物释放到细胞质中进行摄取 使用新型 5-BrHPMPU 前药衍生物作为探针，将其插入每种病毒的病毒 DNA 中。此信息，相关 这五种病毒的稳定性、代谢和体外抗病毒功效数据将提供重要的见解 探究这类新的前药在以下方面具有特殊但不同效力的机制： 研究病毒，同时引入创新的分子工具来确定药物的促进作用 效力。它还有望鉴定出新的、高效的化合物，以便将来开发成有效的 针对这些病毒感染的治疗方法。