STRUCTURAL STUDIES OF FIV PROTEASE INHIBITOR COMPLEXES

我们将使用X射线晶体学来研究 猫免疫缺陷病毒蛋白酶（FIV PR）作为一个程序的基础 旨在开发基于结构和机制的药物 设计 了解FIV PR的分子结构， 这将有助于艾滋病治疗的发展， 抑制HIV-1 PR。首先，FIV PR的分子结构将是 通过基于RSV PR和HIV-1 PR结构的建模得出 在我们的实验室里。 这种模式将有助于 通过实验确定FIV的X射线晶体结构 PR，并用于初步抑制剂设计。 FIV PR的晶体结构 将被确定，unliganded，并作为一个复杂的基板为基础的 抑制剂的 这些信息将用于第一轮的 抑制剂/药物设计。 从第一轮设计中选出的抑制剂 将用于FIV PR-抑制剂复合物的进一步研究。 选择 PR-抑制剂复合物将以非常高的分辨率测定， 为酶-配体定量研究提供了基础 交互. 细化缓蚀剂设计和改进设计工具 将基于以这种迭代方式获得的数据。 FIV PR 将获得的结构与RSV PR和 HIV-1 PR结构，以得出有关结构的一般推论 这些重要的逆转录病毒酶的特性的起源。

We will use X-ray crystallography to study the molecular structure of the Feline Immunodeficiency Virus protease (FIV PR) as the basis for a program aimed at developing the tools for structure and mechanism based drug design. Understanding of the molecular structure of the FIV PR in that context will contribute to the development of AIDS therapeutics based on inhibiting the HIV-1 PR. First, the molecular structure of FIV PR will be worked out by modelling based on the structures of RSV PR and HIV-1 PR determined in our laboratory. Such a model will be useful in experimentally determining the X-ray crystallographic structure of the FIV PR, and for preliminary inhibitor design. The crystal structure of FIV PR will be determined, unliganded and as a complex with substrate-based inhibitors. This information will be used in an initial round of inhibitor/drug design. Inhibitors selected from this first round of design will be used in further studies of the FIV PR-inhibitor complex. Selected PR-inhibitor complexes will be determined to very high resolution to provide the basis for quantitative understanding of enzyme-ligand interactions. Refined inhibitor design and improvement of the design tools will be based on data obtained in this iterative fashion. The FIV PR structures obtained will be compared and contrasted with the RSV PR and HIV-1 PR structures to draw general inferences concerning the structural origins of the properties of these important retroviral enzymes.