Educational Component

本项目拟开发针对炭疽致死因子（LF）的小分子抑制剂。在 在以前的研究中，我们已经开发了两种不同类型的LF抑制剂。抑制剂DR 9 LF-1是一种肽， 高效地定位于LF的活性部位。由化合物1表示的另一个基团是适度的。 在活性位点外结合。本项目旨在将化合物1开发成 有效的候选药物，并提高DR 9 LF-1的稳定性，用于研究这些药物的协同抑制 细胞中的两种抑制剂。具体目标是： 目标1.通过基于结构的设计循环来改善化合物1的效力和药物样性质。我们 计划确定LF-化合物1复合物的晶体结构，并确定 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 设计循环，结合效力、选择性、细胞致死性保护和保护的测定， 动物从LF引起的死亡，将获得更好的药物性能的抑制剂。在晚期， 将测试先导抑制剂的临床前药物性质。 目标二。合成并研究了一种稳定的多肽抑制剂DR 9 LF-2，并将其用于协同抗肿瘤作用的研究。 抑制与LF。新的肽抑制剂DR 9 LF-2被设计为稳定的，但仍然提供C末端基团 将Zn ~（++）螯合在LF的活性部位。在合成并测试该抑制剂的效力后，DR 9 LF-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 细胞和动物的活动。

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.