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.

该项目提议开发针对炭疽致死因子（LF）的小分子抑制剂。在 先前的研究，我们已经开发了两种不同类型的LF抑制剂。抑制剂DR9LF-1是一种肽 用高效力降低到LF的活跃部位。另一组由化合物1表示 有效并在活动地点外绑定。本项目旨在将化合物1开发到 有效的候选药物并提高了DR9LF-1的稳定性，以研究这些研究 细胞中两种抑制剂。具体目的是： 目的1。通过基于结构的设计周期提高化合物1的效力和类似药物的特性。我们 计划确定LF-Compound 1复合物的晶体结构，并确定 化合物1用于抑制。此类信息将用于设计改进的LF抑制剂。重复 设计周期，夫妇与效力，选择性，保护性杀伤力和保护的测定法 LF导致死亡的动物将在抑制剂中获得更好的药物特性。在高级阶段， 将测试铅抑制剂的临床前药物特性。 目标2。合成和研究稳定的肽抑制剂DR9LF-2，并将其用于协同研究 抑制与LF。新的肽抑制剂DR9LF-2设计为稳定，但仍提供C末端组 在LF的活性位点螯合Zn ++。在合成和测试该抑制剂的效力后，DR9LF-2 将与AIM 1中开发的新一代抑制剂一起使用，以研究LF的协同抑制 细胞和动物的活性。