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.

在所有可能对人类造成的生物威胁中，天花是最大的威胁之一。 潜在危险虽然疫苗接种是预防疾病的理想方式，但不良事件 死亡率很高，可以预见。因此，抗病毒药物的开发 治疗天花以及正痘病毒科的其他成员（即猴痘 和天花）是必不可少的。这项工作需要评估新的潜在药物靶点， 潜在抗病毒化合物的通量筛选和新抗病毒化合物的设计 基于敏感靶蛋白的结构。方案2的SERCEB是针对 快速开发治疗正痘病毒疾病的抗病毒疗法，包括三种 项目在项目1中，牛痘病毒酶将在R.莫耶 和M.罗和提交核心F（结构生物学）的三维结构 保持战略定力项目2在E博士的领导下。克恩将利用纯化的牛痘病毒 用于开发高通量抗病毒筛选测定的酶， 补充已经存在的基于细胞的筛选测定。其他潜在的治疗方法将是 通过筛选大量的现有化合物来开发，这些化合物已经通过 与吉利德和奇美里克斯的合作信件。潜在的活性化合物将被进一步研究。 在动物模型中进行评估。项目3，由西克里斯特博士和托内博士领导，三维结构 通过合成化学开发新疗法的数据。此程序的可验证项为 预计在第一年内。具体地说，抗病毒活性已被证明为两个 化合物的种类，在动物模型中建立的活性和合成化学程序， 已开始改进活动。符合临床前毒理学规范的候选药物将被 Whitley博士的NIAID协作抗病毒研究小组进行了评估。