Inhibitors of Ebola Virus Infection

埃博拉病毒感染的抑制剂

• 批准号: 8233436
• 负责人: JAMES CUNNINGHAM
• 金额: $ 52.38万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8233436
• 关键词: Animal Model; Animals; Biological Assay; Cathepsin L; Cathepsins; Cathepsins B; Cell Line; Cysteine Protease; Development; Development Plans; Disease; Disease Outbreaks; Drug Delivery Systems; Ebola virus; Ebola virus envelope glycoprotein; Family; Frankfurt-Marburg Syndrome Virus; Generations; Glycoproteins; Goals; Human; In Vitro; Infection; Knock-out; Lead; Mediating; New England; Peptide Hydrolases; Pharmaceutical Preparations; Pharmacotherapy; Physiological; Property; Protease Inhibitor; Protocols documentation; Resistance; Role; Supportive care; System; Terrorism; Testing; Tissues; Vaccine Therapy; Variant; Viral; Viral Hemorrhagic Fevers; Virus; Virus Diseases; Virus Inhibitors; Virus Replication; base; biodefense; combinatorial chemistry; design; drug development; high throughput screening; in vivo; inhibitor/antagonist; member; mortality; research study; small molecule; small molecule libraries; transmission process

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.

埃博拉病毒（EboV）极易传播并迅速致命，目前还没有有效的疫苗或药物治疗