Drug Design and Synthesis for Orthopoxvirus Infections

正痘病毒感染的药物设计与合成

• 批准号: 7652108
• 负责人: JOHN A SECRIST
• 金额: $ 39.79万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-15 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7652108
• 关键词: Adverse event; Alabama; Animal Model; Antiviral Agents; Antiviral Therapy; Biological Assay; Cells; Chemicals; Class; Collaborations; Collection; Complement; DNA-Directed DNA Polymerase; Data; Development; Disease; Drug Delivery Systems; Drug Design; Endopeptidases; Enzymes; Evaluation; Family; Florida; Goals; Human; Infection; Laboratories; Leadership; Letters; Modality; Monkeypox; Mutate; Mutation; N glycosidase; National Institute of Allergy and Infectious Disease; Orthopoxvirus; Peptide Hydrolases; Pharmaceutical Preparations; Proteins; Research Institute; Research Personnel; Screening procedure; Secure; Smallpox; Structure; Synthesis Chemistry; Testing; Therapeutic; Toxicology; Universities; Vaccination; Vaccinia virus; base; design; disorder prevention; drug discovery; hazard; high throughput screening; improved; in vivo; inhibitor/antagonist; member; mortality; mutant; novel therapeutics; pre-clinical; programs; protein expression; protein structure; skills; structural biology; three dimensional structure

Among all the possible biologic threats to humans, smallpox represents one of the greatest potential hazards. While vaccination is the ideal modality for disease prevention, adverse events are high and mortality can be anticipated. As a consequence, the development of antiviral drugs for the treatment of smallpox as well as other members of the orthopoxvirus family (i.e. monkey pox and variola) are essential. This effort requires evaluation of new potential drug targets, high throughput screening of potential antiviral compounds and design of new antiviral compounds based on the structure of sensitive target proteins. Program 2 of the SERCEB is directed toward the rapid development of antiviral therapies to treat orthopoxvirus diseases and consists of three projects. In Project 1, vaccinia virus enzymes will be expressed in the laboratories of Drs. R. Moyer and M. Luo and submitted to Core F (structural biology) for three-dimensional structure determination. Project 2 under the leadership of Dr. E. Kern will utilize purified vaccinia virus enzymes from Project 1 for the development of high throughput antiviral screening assays to complement already existent cell-based screening assays. Other potential therapeutics will be developed by screening large collections of existing compounds which have been secured through letters of collaboration with Gilead and Chimerix. Potentially active compounds will be further evaluated in animal models. Project 3, led by Drs. Secrist and Toone, three dimensional structure data to develop novel therapeutics through synthetic chemistry. Deliverables from this program are anticipated within the first year. Specifically, antiviral activity has been demonstrated for two classes of compounds, activity established in animal models and a synthetic chemistry program to improve activity initiated. Candidate drugs that meet preclinical toxicology specifications will be evaluated through Dr. Whitley's NIAID Collaborative Antiviral Study Group.

在所有可能对人类的生物学威胁中，天花代表了最伟大的生物威胁之一 潜在危害。虽然疫苗接种是预防疾病的理想方式，但不良事件 很高，可以预期死亡率。结果，开发抗病毒药物 天花以及正托病毒家族的其他成员的处理（即猴子痘 和Variola）至关重要。这项工作需要评估新的潜在药物靶标，高 潜在抗病毒化合物的吞吐量筛选和新抗病毒化合物的设计 基于敏感靶蛋白的结构。 SERCEB的程序2针对 快速开发抗病毒疗法治疗正托病毒疾病，包括三种 项目。在项目1中，将在Drs的实验室中表达离甲酸病毒酶。 R. Moyer 和M. Luo，并提交给三维结构的Core F（结构生物学） 决心。在E. Kern博士的领导下，项目2将利用纯化的离甲酸病毒 项目1的酶用于开发高通量抗病毒筛查测定到 补体已经存在基于细胞的筛选测定法。其他潜在的治疗剂将是 通过筛选大量现有化合物的收集来开发 与Gilead和Chimerix合作的信。潜在的活性化合物将进一步 在动物模型中进行了评估。项目3，由博士领导。秘密和托恩，三维结构 数据以通过合成化学发展开发新的治疗剂。该程序的可交付成果是 预计在第一年内。具体而言，已经证明了抗病毒活性 化合物类别，动物模型中建立的活性以及合成化学计划 改善启动的活动。符合临床前毒理学规范的候选药物将是 通过惠特利博士的NIAID合作抗病毒研究小组进行评估。