NMR OF HIV PROTEASE

HIV蛋白酶的NMR

• 批准号: 3791252
• 负责人: STEPHEN W FESIK
• 金额: --
• 依托单位: ABBOTT LABORATORIES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3791252
• 关键词: amides; binding proteins; chemical binding; deuterium; drug design /synthesis /production; enzyme structure; enzyme substrate complex; human immunodeficiency virus; human immunodeficiency virus 1; human immunodeficiency virus 2; mutant; nitrogen; nuclear magnetic resonance spectroscopy; peptidases; peptide chemical synthesis; protease inhibitor; protein sequence; stable isotope

The maturation of the AIDS virus requires a protease responsible for the cleavage of the gag polyprotein, the precursor of the core structural proteins. Thus, the protease is a promising target for the development of inhibitors therapeutically useful For the treatment of AIDS. The long term goal of this project is to aid in the design of HIV protease inhibitors by providing detailed structural information on HIV protease and protease/inhibitor complexes using NMR spectroscopy. Specifically, we plan to: 1) determine the NH exchange rates of bound peptide inhibitors and compare the amide N and H chemical shifts of the free and enzyme bound inhibitors using isotope-edited proton NMR techniques. 2) perform isotope-edited 2D NOE experiments of protease/inhibitor complexes using isotopically labeled inhibitors to obtain detailed information on inhibitor conformation and active site structure, 3) determine the complete three-dimensional structure of the protease and protease/inhibitor complexes using a variety of 2D and 30 NMR methods, 4) characterize the structure of protease mutants and other AIDS-associated retroviral proteases (e.g., HIV-2).

艾滋病病毒的成熟需要一种蛋白酶负责 用于切割核心前体 gag 多蛋白 结构蛋白。 因此，蛋白酶是一个有希望的靶标。 开发具有治疗作用的抑制剂 治疗艾滋病。 该项目的长期目标是帮助 通过提供详细的信息，在 HIV 蛋白酶抑制剂的设计中 HIV 蛋白酶和蛋白酶/抑制剂的结构信息 配合物使用核磁共振波谱。 具体来说，我们计划：1) 确定结合肽抑制剂的 NH 交换率和 比较游离酶和酶的酰胺 N 和 H 化学位移 使用同位素编辑质子核磁共振技术结合抑制剂。 2） 进行蛋白酶/抑制剂的同位素编辑 2D NOE 实验 使用同位素标记的抑制剂来获得详细的复合物 有关抑制剂构象和活性位点结构的信息， 3）确定完整的三维结构 使用各种 2D 和 30 种 NMR 方法，4) 表征蛋白酶突变体的结构 和其他与艾滋病相关的逆转录病毒蛋白酶（例如 HIV-2）。