STRUCTURALLY-BASED COMBINATORIAL DESIGN OF ANTIVIRALS

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策略，由于病毒倾向于从宿主那里借用催化活性而导致的药物毒性问题而受到阻碍。这项提议的目标是开发促进使用病毒和病毒蛋白质的高分辨率结构的替代方法，以设计促进使用病毒和病毒蛋白质的高分辨率结构来设计针对病毒特异性大分子相互作用的抗病毒药物。所提出的方法是标准的基于结构的设计方法和组合化学的混合体。在这种混合方法中，目标结构被用来为化合物的结构偏向组合文库衍生模板，并对这些文库进行筛选，以寻找具有所需抗病毒活性的特定化合物。该方法绕过了标准基于结构的设计方法固有的限制，这些限制源于大分子结构测定的缺乏精确度，无法考虑大分子靶标的灵活性，以及当前计算方法无法预测大范围配体和靶标的真实结合自由能。通过将结构信息融入到图书馆设计中，该方法将图书馆的多样性集中在更有可能产生生产力的领域，消除了传统无偏见组合方法的非常大的多样性所产生的一些问题(和偶尔的人工制品)。这些方法将用于解决三个具体目标：1)设计结合脊髓灰质炎病毒衣壳和相关肠道病毒和鼻病毒并抑制与细胞进入相关的构象变化的试剂。2)干扰单纯疱疹病毒DNA聚合酶及其辅助蛋白UL42之间相互作用的试剂的设计，UL42是进行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形成功能性寡聚体的药物。

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.