GPCR antagonists as anti-Ebola virus entry inhibitors

GPCR 拮抗剂作为抗埃博拉病毒进入抑制剂

• 批准号: 8980076
• 负责人: Lijun Rong
• 金额: $ 29.94万
• 依托单位: MICROBIOTIX, INC
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8980076
• 关键词: Affinity; Africa; Animal Model; Animals; Anti-Cholinergics; Antihistamines; Antiviral Therapy; Benztropine; Biological Assay; CCR5 gene; Categories; Cells; Cessation of life; Clinical; Development; Disease; Disease Outbreaks; Dose; Drug Kinetics; Ebola virus; Epidemic; Exhibits; Family; Filoviridae; Filovirus; Frankfurt-Marburg Syndrome Virus; G-Protein-Coupled Receptors; Glycoproteins; HIV; HIV Entry Inhibitors; HIV Envelope Protein gp120; Human; Immune response; In Vitro; Infection; Infection Control; Inhibitory Concentration 50; Lead; Libraries; Liver Microsomes; Mediating; Modification; Mus; Nature; Oral; Parkinson Disease; Pathogenesis; Permeability; Phase; Primates; Property; Protein Isoforms; Protocols documentation; Research; Safety; Solubility; Structure; Structure-Activity Relationship; T-20; Therapeutic; Time; TimeLine; Tissues; Toxic effect; United States National Institutes of Health; Vaccination; Vaccine Therapy; Vaccines; Viral; Viral Hemorrhagic Fevers; Virus; Virus Diseases; Virus Inhibitors; Work; aqueous; base; cytotoxicity; glycoprotein G; improved; inhibitor/antagonist; member; mortality; nonhuman primate; pathogen; pre-clinical; prevent; public health relevance; receptor; research study; small molecule; small molecule libraries; stem; therapeutic target; vaccine candidate

 DESCRIPTION (provided by applicant): Ebola (EBOV) and Marburg (MARV) viruses belong to the family Filoviridae and can cause fatal hemorrhagic fevers characterized by widespread tissue destruction with an incubation period of 4-14 days. Because of the safety concerns, these viruses are designated as biosafety level 4 agents. Currently there is no effective vaccine or therapeutic treatment against filoviral infection and pathogenesis in humans. The current ongoing 2014 Ebola epidemic in West Africa has led to more than 5,000 deaths and underscores the global challenge of treating and controlling this deadly virus. This application defines a plan to identify and develop potent small molecule inhibitors, which block entry of EBOV into host cells. We have developed a cell-based HTS protocol targeting Ebola entry to identify small molecule inhibitors that block entry of infectious EBOV. The overall objective of this Phase I application is to identify and develop these inhibitors as potential anti-Ebola therapeutics. This application will focus on the following three specific aims: (1) Identify potent anti-Ebola inhibitors from a small molecule library of GPCR antagonists, prioritize and chemically modify the most potent inhibitors based on structure-activity relationships (SARs) to improve potency and selectivity. (2) Validate the lead inhibitor candidates in the infectious assay and investigate the mechanism of action (MOA) of the EBOV inhibitors. (3) Select EBOV inhibitors with in vitro ADME properties suitable for i.v. and oral dosing.