Cathepsin B Inhibitors as Therapeutics for Ebola Infection

组织蛋白酶 B 抑制剂治疗埃博拉感染

• 批准号: 8980049
• 负责人: Doron Greenbaum
• 金额: $ 22.24万
• 依托单位: PHELIX THERAPEUTICS, LLC
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8980049
• 关键词: Africa; Amino Acids; Area; Binding; Biological Assay; Biomimetics; Capsid Proteins; Caspase; Categories; Cathepsins; Cathepsins B; Cell membrane; Cell model; Cells; Cessation of life; Cleaved cell; Collaborations; Computer Simulation; Cysteine Proteinase Inhibitors; Cytoplasm; Data; Development; Disease; Disease Outbreaks; Ebola virus; Endosomes; Enzyme Inhibitor Drugs; Enzyme Inhibitors; Enzymes; Evaluation; FDA approved; Family; Filovirus; Genes; Genomics; Glycoproteins; Goals; Hela Cells; Human; Human Activities; Infection; Intellectual Property; Invaded; Laboratories; Lead; Letters; Libraries; Life; Life Cycle Stages; Literature; Malignant Neoplasms; Mammals; Medical; Metabolic; Modeling; Morbidity - disease rate; Osteoporosis; Patients; Peptide Hydrolases; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Positioning Attribute; Prevention; Process; Proteins; Proteolysis; RNA Viruses; Research; Risk; Side; Spain; Techniques; Testing; Therapeutic; Therapeutic Agents; Toxic effect; Travel; United States; Viral; Viral Hemorrhagic Fevers; Virion; Virus; Virus Diseases; Virus Inhibitors; Virus Replication; Work; base; counterscreen; crosslink; drug discovery; indexing; inhibitor/antagonist; interest; meetings; member; mimetics; mortality; nonhuman primate; pathogen; pre-clinical; programs; public health relevance; scaffold; therapeutic development; viral resistance

 DESCRIPTION (provided by applicant): Ebola virus (EBOV) of the filovirus family is an enveloped, single-stranded RNA virus that causes severe hemorrhagic fever in multiple mammals including humans and non-human primates. The recent 2013-2014 outbreak of EBOV in West Africa has resulted in the deaths of nearly 40% of infected patients to date, spreading throughout West Africa and internationally to the United States and Spain via travelers. Therefore, it is essential to understand how this virus invades its hosts and causes disease, to spur approaches to treatment and prevention. Because entry into host cells is the first step in the viral life cycle, this area offers a major target for treatment and prevention. Importantly, ithas been demonstrated that EBOV requires the activity of human Cathepsin B (CatB) for sequential processing of its glycoprotein GP1. The fact that EBOV utilizes this key human protease, CatB, for entry offers an opportunity to develop anti-EBOV inhibitor drugs. We aim to generate potent, specific inhibitors for CatB via exploration of the prime side -helical binding pocket that resuts in inhibition of EBOV infection in live cell assays.

 描述（由申请方提供）：丝状病毒科的埃博拉病毒（EBOV）是一种有包膜的单链RNA病毒，可在多种哺乳动物（包括人类和非人灵长类动物）中引起重度出血热。最近2013-2014年西非爆发的埃博拉病毒迄今已导致近40%的感染患者死亡，通过旅行者在整个西非和国际上传播到美国和西班牙。因此，了解这种病毒如何侵入宿主并导致疾病，以刺激治疗和预防方法至关重要。由于进入宿主细胞是病毒生命周期的第一步，因此该区域提供了治疗和预防的主要目标。重要的是，已经证明EBOV需要人组织蛋白酶B（CatB）的活性来连续加工其糖蛋白GP 1。EBOV利用这种关键的人类蛋白酶CatB进入的事实为开发抗EBOV抑制剂药物提供了机会。我们的目标是通过探索导致在活细胞测定中抑制EBOV感染的引发侧β-螺旋结合口袋来产生CatB的有效的特异性抑制剂。