MOLECULAR AND STRUCTURAL APPROACHES TO ANTIVIRALS

使用传统的基于目标的设计策略来识别 临床上有用的抗病毒剂已经受到以下趋势的阻碍： 大多数候选抗病毒剂是高毒性的。 毒性产生 由于病毒明显倾向于“借用” 宿主，导致潜在病毒靶标之间的显著同源性 和细胞同源物。 领域的最新发展 基于结构的药物设计的计算方法，提供 这是一个机会，设计大分子配体的基础上的结构， 单独靶分子，而无需参考已知底物，或 抑制剂的 这些方法仍处于开发阶段，可能 允许设计具有显著较低交叉的抗病毒剂， 与宿主基本功能的反应性。 本申请建议 继续开展结构- 的方法来设计抗病毒药物靶向几个井- 表征脊髓灰质炎病毒的靶蛋白，包括衣壳本身， 病毒RNA依赖性RNA聚合酶（3D）和蛋白酶聚合酶 前体（3CD），其在病毒生命周期中起多种作用;以及 将设计研究扩展到一个新的目标， 丁型肝炎病毒（HDV）的衣壳蛋白。 初步研究已经 结果确定了六种脊髓灰质炎病毒/衣壳的结构， 结合药物复合物，设计一类新的衣壳结合药物 使用MCSS程序（由Miranker和Karplus开发）， HDV衣壳蛋白的寡聚化结构域的结晶。 这些研究将扩大到启动第二轮设计， 衣壳结合药物，以扩大使用MCSS设计抑制剂， 3D，以结晶和解决3CD的结构，并使用新的 设计抑制其蛋白水解和RNA结合的试剂 活性，并解决HDV肽的结构，并使用该 结构来设计阻断衣壳蛋白组装的试剂 并作为疫苗设计的基础。 为了方便并发 应用程序和计算设计方法的开发， 所有设计研究将与药物设计合作进行， Martin Karplus的实验室。

The use of traditional target-based design strategies to identify clinically useful antiviral agents has been hampered by the tendency of most candidate antiviral agents to be highly toxic. The toxicity arises due to an apparent tendency of viruses to "borrow" functions from the host, resulting in significant homologies between potential viral targets and cellular homologues. Recent developments in the field of computational methods for structure-based drug design, provide the opportunity to design macromolecular ligand based on the structure of the target molecule alone without necessary reference to known substrates or inhibitors. These methods, which are still in the development stage, may permit the design of antiviral agents with significantly lower cross- reactivity with essential host functions. This application proposes to continue a program of joint development and applications of structure- based methods to design antiviral agents targeting several well- characterized target proteins of poliovirus, including the capsid itself, the viral RNA-dependent RNA polymerase (3D), and a protease-polymerase precursor (3CD) which plays multiple roles in the viral life cycle; and to extend design studies to a new target, the oligomerization domain of the capsid protein of hepatitis delta virus (HDV). Preliminary studies have resulted in the determination of the structures of six poliovirus/capsid- binding drug complexes, the design of a new class of capsid binding drug using the program MCSS (developed by Miranker and Karplus), and the crystallization of oligomerization domain of the HDV capsid protein. These studies will be extended to initiate a second round of design of capsid binding drugs, to extend the use of MCSS to design inhibitors of 3D, to crystallize and solve the structure of 3CD and use the new structure to design agents which inhibit its proteolytic and RNA binding activities, and to solve the structure of the HDV peptide and use this structure to design agents which block the assembly of the capsid protein and as a basis of vaccine design. In order to facilitate the concurrent development of the application and the computational design methodologies, all design studies will be performed in collaboration with the drug-design group in Martin Karplus's laboratory.