Inhibitors of Ebola Virus Infection

埃博拉病毒(EBOV)很容易传播并迅速致死，目前还没有有效的疫苗或药物疗法 最近的实验表明，EBOV感染的生理触发因素是逐步的蛋白分解裂解醇。 组织蛋白酶L和组织蛋白酶B的包膜糖蛋白(GP) 半胱氨酸蛋白酶。重要的是，具有良好特性的组织蛋白酶小分子抑制剂显著 体外抑制EBOV感染(&gt；99%)。这项提议的目标是开发Cathepsir的潜力 作为抗EBOV药物的抑制剂。 具体目标#1：开发抑制EBOV gp依赖感染的小分子管道 A.筛选主要类别的组织酶抑制剂的化合物，以确定具有抗肿瘤作用的先导化合物 EBOV活动。包括已经在开发的针对其他疾病的抑制剂。 B.确定高通量鉴定的198种EBOV-GP感染特异性抑制剂中是否有任何一种 筛选出40,000个小分子是组织蛋白酶抑制剂或与它们协同作用。 C.在现有的动物模型中确定有希望的先导化合物的抗EBOV活性。 具体目标2：确定组织蛋白在EBOV感染中的作用。 A.使用选择性抑制剂和基因敲除来源的细胞系来识别所有介导EBOV的组织蛋白 和马尔堡病毒感染。 B.确定在EBOV复制高的宿主组织中介导感染的组织蛋白酶。 C.开发基于BL3的系统，以选择和分析依赖于特定基因的EBOV变体 组织蛋白酶和/或对特定的抑制剂具有抗药性。 具体目标#3：作为药物开发的一部分，设计、合成和测试第二代EBOV抑制剂 计划。SA 1-2将通知迭代Lead优化协议的起点，以确定最高 选择性组织酶抑制剂，保持有效和广泛的抗EBOV活性。

Ebola virus (EboV) is readily transmitted and rapidly fatal, and there is no effective vaccine or drug therapy Recent experiments reveal that the physiological trigger for EboV infection is stepwise proteolytic cleavage ol the envelope glycoprotein (GP) by cathepsin L and cathepsin B, two members of a family of endosoma cysteine proteases. Importantly, well-characterized small molecule inhibitors of cathepsin proteases markedly inhibit EboV infection in vitro (>99%). The goal of this proposal is to develop the potential of cathepsir inhibitors as anti-EboV drugs. Specific Aim #1: Develop pipeline of small molecules that inhibit EboV GP-dependent infection a. Screen compounds in major classes of cathepsin inhibitors to identify lead compounds with anti- EboV activity. Include inhibitors already under development for other disorders. b. Determine if any of the 198 specific inhibitors of EboV-GP infection identified by high-throughput screen of 40,000 small molecules are cathepsin inhibitors or function synergistically with them. c. Determine anti-EboV activity of promising lead compounds in existing animal models. Specific Aim #2: Determine role of cathepsins in EboV infection. a. Use selective inhibitors and knockout-derived cell lines to identify all cathepsins that mediate EboV and Marburg virus infection. b. Identify the cathepsins that mediate infection of host tissues where EboV replication is high. c. Develop BL3-based system to select and analyze EboV variants that are dependent on specific cathepsins and/or are resistant to specific inhibitors. Specific Aim #3: Design, synthesize and test second generation EboV inhibitors as part of drug development plan. SA 1-2 will inform the starting point for an iterative lead optimization protocol to identify the most highly selective cathepsin inhibitors that retain potent and broad anti-EboV activity.