STRUCTURALLY-BASED COMBINATORIAL DESIGN OF ANTIVIRALS

基于结构的抗病毒药物组合设计

• 批准号: 6095854
• 负责人: JAMES M HOGLE
• 金额: $ 37.4万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-07-01 至 2005-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6095854
• 关键词: Alphaherpesvirinae; DNA directed DNA polymerase; Enterovirus; X ray crystallography; antiviral agents; capsid; chemical binding; chemical structure function; combinatorial chemistry; drug design /synthesis /production; hepatitis D virus; high throughput technology; method development; molecular site; peptide library; poliovirus; rhinovirus; virion; virus protein

The use of traditional mechanism-based design strategies to design strategies to design antiviral agents targeting viral enzymatic activities has been hampered by problems with toxicity of the agents resulting from the tendency of viruses to "borrow" catalytic activities from the host. The goal of this proposal is to develop alternative methodologies that facilitate the use of high resolution structures of viruses and viral proteins to design alternative methodologies that facilitate the use of high-resolution structures of viruses and viral proteins to design antiviral agents that target virus-specific macromolecular interactions. The methodologies proposed are a hybrid between standard structure-based design methods and combinatorial chemistry. In this hybrid approach the target structure is used to derived a template for structurally biased-combinatorial libraries of compounds, and these libraries are screened for specific compounds with the desired antiviral activity. The method by-passes limitations inherent to standard structure-based design methods arising from lack of precision in macromolecular structure determinations, the inability to account for flexibility of the macromolecular target, and the inability of current computational methods to predict realistic free- energies of binding for a broad range of ligands and targets. By incorporating structural information into the library design the method focuses the diversity of the library on areas that are more likely to be productive, eliminating some of the problems (and occasional artifacts) generated by the very large diversity of the conventional unbiased combinatorial approaches. The methods will be used to address three specific goals: 1) The design of agents that bind the capsid of poliovirus and related entero- and rhinoviruses and inhibit conformational changes associated with cell entry. 2) The design of agents that interfere with an interaction between the herpes simplex virus DNA polymerase and its accessory protein UL42 which is required for processive DNA replication and infectivity. 3) The design of agents that bind to monomers or dimers of the major protein of hepatitis D virus and prevent the formation of functional oligomers.

使用传统的基于机制的设计策略来设计针对病毒酶活性的抗病毒药物的设计策略受到了由于病毒从宿主“借用”催化活性的倾向而导致的药物毒性问题的阻碍。该提案的目标是开发替代方法，以促进使用病毒和病毒蛋白的高分辨率结构来设计替代方法，以促进使用病毒和病毒蛋白的高分辨率结构来设计针对病毒特异性的抗病毒剂大分子相互作用。所提出的方法是基于标准结构的设计方法和组合化学之间的混合。在这种混合方法中，目标结构用于衍生化合物结构偏向组合文库的模板，并在这些文库中筛选具有所需抗病毒活性的特定化合物。该方法绕过了基于标准结构的设计方法固有的局限性，这些局限性是由于大分子结构测定缺乏精度、无法考虑大分子目标的灵活性以及当前计算方法无法预测实际的结合自由能而产生的。适用于广泛的配体和靶标。通过将结构信息纳入库设计中，该方法将库的多样性集中在更有可能高效的领域，消除了传统无偏组合方法的巨大多样性所产生的一些问题（以及偶尔的伪影）。这些方法将用于实现三个具体目标：1）设计结合脊髓灰质炎病毒和相关肠病毒和鼻病毒衣壳并抑制与细胞进入相关的构象变化的药物。 2) 干扰单纯疱疹病毒 DNA 聚合酶与其辅助蛋白 UL42 之间相互作用的试剂的设计，这是进行性 DNA 复制和感染性所必需的。 3)设计与丁型肝炎病毒主要蛋白的单体或二聚体结合并防止功能性寡聚体形成的试剂。