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.

项目摘要 美国国立卫生研究院已经确定了一组传染性病毒为“新兴”，因为它们对公众的威胁越来越大。 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 疾病，但很少有药物已被批准用于这类病原体。西多福韦（Cidofovir，CDV，HPMPC）是一种无环 已知核苷膦酸酯（ANP）对一系列DNA病毒表现出活性。然而，像其他 作为一类ANP，CDV具有显著的缺点，包括固有地缺乏口服生物利用度，相对低， 效力和肾毒性。CDV的N-烷基酪氨酸酰胺前药及其腺嘌呤类似物HPMPA 最近由PI设计和合成，南加州大学的查尔斯·麦肯纳教授 (USC)与亲本相比，对CMV和几种其它DNA病毒的体外效力大大增强 药物和改进的选择性指数。效价、选择性和有效性的重要病毒依赖性变化 观察到增强，这还没有被机械地解释。在这个R21项目中，这些前药 一系列具有修饰的前体结构的类似物被设计成影响磷脂酶C的活化， 评价在生理条件下的稳定性和渗透性以及抗CMV，HSV 1， VACV和两种新出现的DNA病毒：HHV-6 B和BK病毒。研究将集中在将个人 前体结构特征与被感染细胞的摄取和药物释放到细胞质中用于摄取 每种病毒的病毒DNA，使用新的5-BrHMPU前药衍生物作为探针。这些信息，相关 这五种病毒的稳定性、代谢和体外抗病毒效力数据将提供重要的见解 这类新的前药在以下方面的特殊但不同的效力的潜在机制 研究的病毒，同时引入了一种创新的分子工具来确定药物前体 有效性它还有望确定新的，高效的化合物，用于未来开发有效的 治疗这些病毒感染的方法。