Furopyrimidines as novel inhibitors of henipaviruses

呋喃嘧啶作为亨尼帕病毒的新型抑制剂

基本信息

批准号：
10327725
负责人：
Lijun Rong
金额：
$ 29.97万
依托单位：
CHICAGO BIOSOLUTIONS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-11 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10327725
关键词：
Affinity Animal Model Animal Testing Animals Antiviral Agents Australia Biological Assay Case Fatality Rates Cell Line Communicable Diseases Computer software Containment Development Disease Outbreaks Drug Kinetics Exhibits Far East Future Hendra Virus Henipavirus Henipavirus Infections Human In Vitro Lead Libraries Livestock Luciferases Mammals Measurement Modification Nipah Virus Paramyxovirus Permeability Phase Property Protein Isoforms Public Health Quinazolines Recombinants Research Respiratory Disease Series Structure Structure-Activity Relationship Supportive care System Toxic effect Tropism Vaccines Vero Cells Virus Virus Diseases Virus Replication Zoonoses analog base biothreat cell type clinical candidate cytotoxicity design drug discovery efficacy validation high throughput screening improved in vitro Assay indexing inhibitor lead optimization mouse model nanomolar nervous system disorder novel nursing technique pathogen pathogenic virus scaffold small molecule small molecule inhibitor

项目摘要

The emergence and reemergence of pathogenic viruses represent continuous infectious disease threats to public health. Among these, the paramyxoviruses, which include many important human and animal pathogens, also include two excellent examples of emerged, zoonotic viral pathogens of importance: the henipaviruses; Hendra virus (HeV) and Nipah virus (NiV). HeV and NiV have a uniquely broad host tropism capable of infecting at least 18 animal species across 6 orders of mammals. HeV and NiV can also cause a systemic and often fatal respiratory and/or neurological disease in 11 mammalian species including humans. These henipaviruses remain significant biothreats to humans and economically important livestock in Australia and throughout South East Asia. In addition, there are no vaccines or antivirals approved for human use. Thus new treatment options are urgently needed. This application defines a plan to develop potent, small molecule inhibitors, which inhibit henipavirus replication. We have identified compounds that inhibit replication of these viruses, with IC50 values in the nanomolar range. In this application, we propose three specific aims: (1) To optimize the lead (and backup) scaffold and select developmental candidates; (2) Develop the SAR in the henipavirus infectious assay and further investigate the mechanism of action (MOA) of the replication inhibitors; and (3) Select henipavirus inhibitors with in vitro ADME properties suitable for whole animal testing in an infectious animal model.

病原病毒的出现和重新出现代表了持续的传染病威胁为了公共卫生。其中，副粘病毒包括许多重要的人类和动物病毒病原体，还包括出现的两个重要的人畜共患病毒病原体的绝佳例子：亨尼帕病毒；亨德拉病毒（HeV）和尼帕病毒（NiV）。 HeV 和 NiV 拥有独特的广泛宿主能够感染 6 目哺乳动物中至少 18 种动物。 HeV 和 NiV 可以还会导致 11 种哺乳动物出现系统性且往往致命的呼吸系统和/或神经系统疾病包括人类。这些亨尼帕病毒仍然对人类和经济构成重大生物威胁澳大利亚和整个东南亚的重要牲畜。此外，目前还没有疫苗或批准用于人类的抗病毒药物。因此迫切需要新的治疗方案。这个应用程序制定了开发有效的小分子抑制剂的计划，该抑制剂可抑制亨尼帕病毒的复制。我们有鉴定出抑制这些病毒复制的化合物，其 IC50 值在纳摩尔范围内。在此应用中，我们提出了三个具体目标：（1）优化主（和备用）脚手架和选择发展候选人； (2) 开发亨尼帕病毒感染检测中的SAR并进一步研究复制抑制剂的作用机制（MOA）； (3) 选择亨尼帕病毒具有体外 ADME 特性的抑制剂，适合在感染性动物模型中进行整体动物测试。