Educational Component

教育部分

• 批准号: 7696157
• 负责人: A Darise Farris
• 金额: $ 11.84万
• 依托单位: OKLAHOMA MEDICAL RESEARCH FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7696157
• 关键词: 2-cyclopentyl-5-(5-isoquinolylsulfonyl)-6-nitro-1H-benzo(D)imidazole; Active Sites; Animals; Anthrax disease; Antibiotic Therapy; Antibiotics; Bacillus anthracis; Binding; Binding Sites; Biological Assay; Breathing; C-terminal; Cause of Death; Cells; Clinical Treatment; Complex; Coupled; Crystallography; Data; Development; Generations; HIV Protease; Hand; Human; Human body; Hydrolysis; Immunologics; Individual; Infection; Kinetics; Lead; Length; Libraries; Life; Metalloproteases; Molecular; Patients; Peptide Hydrolases; Peptides; Peptidyl-Dipeptidase A; Pharmaceutical Chemistry; Pharmaceutical Preparations; Plant Roots; Preclinical Testing; Property; Renin; Screening procedure; Site; Staging; Structure; Substrate Specificity; Symptoms; Testing; Therapeutic; Time; Toxic effect; Work; anthrax lethal factor; base; beta secretase; chelation; design; drug candidate; drug development; hydroxamate; improved; inhibitor/antagonist; mortality; small molecule; therapeutic target

This project proposes to develop small-molecular inhibitors against the lethal factor (LF) of anthrax. In previous studies, we have developed two different types of LF inhibitors. Inhibitor DR9LF-1 is a peptide that Dinds to the active site of LF with high potency. The other group, represented by compound 1, is moderately potent and binds outside the active site. The present project is designed to develop compound 1 into a potent drug candidate and improve the stability of DR9LF-1 for the studies of synergistic inhibition of these two types of inhibitors in cells. The Specific Aims are: Aim 1. To improve potency and drug-like properties of compound 1 by structure-based design cycles. We plan to determine the crystal structure of LF-compound 1 complex and determine the essential group in compound 1 for inhibition. Such information will be utilized to design improved LF inhibitors. The repeat of the designing cycles, couple with assays for potency, selectivity, protection of cellular lethality and protection of animal from LF caused death, will acquire better drug properties in the inhibitors. At an advanced stage, the lead inhibitors will be tested for preclinical drug properties. Aim 2. To synthesize and study a stable peptide inhibitor, DR9LF-2, and use it in the study of synergistic inhibition vs. LF. New peptide inhibitor DR9LF-2 is designed to be stable but still provide a C-terminal group to chelate Zn++ in the active site of LF. After the synthesis and testing of this inhibitor for potency, DR9LF-2 will be used with new generations of inhibitors developed in Aim 1 for the study of synergistic inhibition of LF activities in cells and animals.

该项目拟开发针对炭疽致死因子（LF）的小分子抑制剂。在 在之前的研究中，我们开发了两种不同类型的LF抑制剂。抑制剂 DR9LF-1 是一种肽， 高效作用于 LF 的活性位点。另一组，以化合物 1 为代表，具有中等程度的 有效并结合在活性位点之外。本项目旨在将化合物 1 开发成 有效的候选药物并提高 DR9LF-1 的稳定性，用于这些药物的协同抑制研究 细胞内有两种类型的抑制剂。具体目标是： 目标 1. 通过基于结构的设计周期提高化合物 1 的效力和类药特性。我们 计划确定LF-化合物1配合物的晶体结构并确定其中的必要基团 化合物1用于抑制。这些信息将用于设计改进的 LF 抑制剂。的重复 设计周期，结合效力、选择性、细胞致死性保护和保护的测定 LF 导致的动物死亡，将在抑制剂中获得更好的药物特性。在高级阶段， 将测试先导抑制剂的临床前药物特性。 目的2.合成并研究稳定的肽抑制剂DR9LF-2，并将其用于协同作用的研究 抑制与 LF。新型肽抑制剂 DR9LF-2 设计稳定，但仍提供 C 端基团 在 LF 的活性位点螯合 Zn++。在合成并测试该抑制剂的效力后，DR9LF-2 将与目标1中开发的新一代抑制剂一起用于LF的协同抑制研究 细胞和动物中的活动。