Optimizing Ridaifen-B analogs as potential therapeutics for Ebola viruses

优化 Ridaifen-B 类似物作为埃博拉病毒的潜在疗法

• 批准号: 10586633
• 负责人: Lijun Rong
• 金额: $ 79.52万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-20 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10586633
• 关键词: Animal Model; Antiviral Therapy; Binding; Biological Assay; Bundibugyo virus; Characteristics; Chemicals; Clinic; Complex; Democratic Republic of the Congo; Dose; Drug Kinetics; Ebola; Ebola Hemorrhagic Fever; Ebola virus; Estrogen Receptors; Exhibits; GP2 gene; GTPBP1 gene; Glycoproteins; Goals; Human; In Vitro; Incidence; Infection; Lead; Libraries; Life; Ligands; Maximum Tolerated Dose; Mediating; Medical; Mus; Pharmaceutical Preparations; Prevalence; Property; Reporting; Research; Resolution; Reston Ebola virus; Route; Safety; Selective Estrogen Receptor Modulators; Series; Structure; Sudan; Sudan Ebola virus; Tamoxifen; Therapeutic; Time; Toremifene; Toxicokinetics; Viral; Viral Hemorrhagic Fevers; Viral Pathogenesis; Virus; Virus Diseases; Work; Zoonoses; analog; antiviral drug development; base; cost; efficacy evaluation; forest; guinea pig model; in vivo evaluation; inhibitor; lead optimization; mortality; nonhuman primate; novel; pre-clinical; prophylactic; remote location; scaffold; scale up; side effect; small molecule; small molecule inhibitor; small molecule libraries; therapeutic candidate; therapeutic target; therapeutically effective

Summary Ebola virus disease (EVD) is caused by an infection with a group of viruses within the genus Ebolavirus. There are at least five species of Ebolavirus, Ebola virus (Zaire, EBOV), Ebola Sudan (SUDV), Bundibugyo virus (BDBV), Reston virus and Tai Forest virus (TAFV). Infections with these viruses can cause severe hemorrhagic fevers in humans and nonhuman primates, and are associated with up to 90% mortality rates with EBOV. Because of the safety concerns, these viruses are designated as the biosafety level 4 agents. Currently there is no effective therapeutic treatments against Ebola virus infection and pathogenesis in humans. Thus the goal of this application is to develop GP-specific small molecule inhibitors as drugs which can be used prophylactically and therapeutically against EBOV and other Ebola virus infections. To achieve this, we screened an in-house library of small molecules, and identified numerous potent entry inhibitors against EBOV. We have identified a series of potent compounds and will use them as leads which will be chemically optimized and developed as an anti-Ebola virus therapy candidate. In this application, two specific aims are proposed: (1) structure- based optimization of the lead compounds, and (2) In vivo evaluation of the lead compounds against EBOV infection using animal models.

概括 埃博拉病毒病（EVD）是由体内一组病毒感染引起的 埃博拉病毒属。埃博拉病毒至少有五种，埃博拉病毒（扎伊尔、 EBOV）、苏丹埃博拉病毒（SUDV）、本迪布焦病毒（BDBV）、雷斯顿病毒和泰森林病毒 病毒（TAFV）。这些病毒的感染可导致严重的出血热 人类和非人类灵长类动物，并且与高达 90% 的死亡率相关 埃博拉病毒。出于安全考虑，这些病毒被指定为生物安全病毒 4级特工。目前尚无针对埃博拉病毒的有效治疗方法 人类感染和发病机制。因此，该应用程序的目标是开发 GP特异性小分子抑制剂作为药物，可用于预防和治疗 治疗埃博拉病毒和其他埃博拉病毒感染。为了实现这一目标，我们 筛选了内部小分子库，并确定了许多有效的条目 埃博拉病毒抑制剂。我们已经鉴定出一系列有效的化合物并将使用 它们作为先导物质，将经过化学优化并开发为抗埃博拉病毒 治疗候选者。在本申请中，提出了两个具体目标：（1）结构- 基于先导化合物的优化，以及（2）先导化合物的体内评估 使用动物模型对抗埃博拉病毒感染的化合物。