Furopyrimidines as novel inhibitors of henipaviruses

呋喃嘧啶作为亨尼帕病毒的新型抑制剂

• 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
• 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

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.

致病病毒的出现和重新出现代表了持续的传染病威胁 对公众健康。其中，副粘病毒，包括许多重要的人类和动物， 病原体，还包括两个很好的例子出现，人畜共患病毒病原体的重要性： 亨德拉病毒（HeV）和尼帕病毒（NiV）。HeV和NiV具有独特的广泛宿主 嗜性能够感染6个哺乳动物目中至少18种动物。HeV和NiV可以 还导致11种哺乳动物的全身性和致命的呼吸和/或神经疾病 包括人类这些亨尼帕病毒仍然是人类和经济上的重大生物威胁 澳大利亚和整个东南亚的重要牲畜。此外，没有疫苗或 被批准用于人类的抗病毒药。因此，迫切需要新的治疗选择。本申请 定义了一个计划，以开发有效的，小分子抑制剂，抑制亨尼帕病毒的复制。我们有 鉴定了抑制这些病毒复制的化合物，IC 50值在纳摩尔范围内。 在本申请中，我们提出了三个具体目标：（1）优化铅（和备份）支架， 选择开发候选物;（2）在亨尼帕病毒感染性测定中开发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性质的抑制剂，适用于感染性动物模型中的全动物试验。