Inhibitors of Ebola Virus Infection

埃博拉病毒（EboV）易于传播并迅速致命，目前还没有有效的疫苗或药物治疗 最近的实验表明，EboV感染的生理触发因素是逐步的蛋白水解裂解。 被膜糖蛋白（GP）由组织蛋白酶L和组织蛋白酶B，一个胞内体家族的两个成员 半胱氨酸蛋白酶重要的是，组织蛋白酶蛋白酶的充分表征的小分子抑制剂显著地 体外抑制EboV感染（>99%）。该提案的目的是开发cathepsir的潜力 抑制剂作为抗EboV药物。 具体目标#1：开发抑制EboV GP依赖性感染的小分子管道 a.筛选组织蛋白酶抑制剂的主要类别中的化合物，以鉴定具有抗组织蛋白酶活性的先导化合物。 EboV活性。包括已经在开发中的用于其他疾病的抑制剂。 B.确定是否有任何的198个特异性抑制剂的EboV-GP感染所确定的高通量 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.在现有动物模型中确定有前景的先导化合物的抗EboV活性。 具体目标#2：确定组织蛋白酶在EboV感染中的作用。 a.使用选择性抑制剂和敲除衍生的细胞系来鉴定介导EboV的所有组织蛋白酶 和马尔堡病毒感染。 B.鉴定介导EboV复制高的宿主组织感染的组织蛋白酶。 C.开发基于BL 3的系统，以选择和分析依赖于特定 组织蛋白酶和/或对特异性抑制剂有抗性。 具体目标#3：设计、合成和测试第二代EboV抑制剂，作为药物开发的一部分 计划SA 1-2将通知迭代导联优化方案的起点，以确定最高 选择性组织蛋白酶抑制剂保留了有效和广泛的抗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.