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

基本信息

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
项目类别：
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

项目摘要

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.

概括埃博拉病毒疾病（EVD）是由一组病毒感染引起的埃博拉病毒属。至少有五种埃博拉病毒，埃博拉病毒（Zaire， EBOV），埃博拉苏丹（SUDV），Bundibugyo病毒（BDBV），雷斯顿病毒和太极森林病毒（TAFV）。这些病毒感染会导致严重的出血性发作人类和非人类灵长类动物，与多达90％的死亡率有关 EBOV。由于安全问题，这些病毒被指定为生物安全 4级代理。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理。因此，此应用的目的是开发 GP特异性的小分子抑制剂作为可预防和可预防使用的药物在治疗上针对EBOV和其他埃博拉病毒感染。为了实现这一目标，我们筛选了一个小分子的内部库，并确定了许多有效的入口针对EBOV的抑制剂。我们已经确定了一系列有效的化合物，并将使用它们是将化学优化和开发为抗欧博拉病毒的铅治疗候选人。在此应用中，提出了两个具体目标：（1）结构 - 基于铅化合物的优化和（2）铅的体内评估使用动物模型针对EBOV感染的化合物。