Development of group 2 influenza A virus entry inhibitors

2 组甲型流感病毒侵入抑制剂的开发

基本信息

批准号：
9903216
负责人：
Lijun Rong
金额：
$ 30万
依托单位：
CHICAGO BIOSOLUTIONS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9903216
关键词：
Affect Affinity Amantadine Animal Model Animal Testing Anti-influenza Agent Antiviral Agents Biological Assay Cells Centers for Disease Control and Prevention (U.S.)Cessation of life Communicable Diseases Development Dose Drug Kinetics Effectiveness Epidemic Exhibits Family Genome Goals Grant H7 hemagglutinin Health Hemagglutinin Immunocompromised Host In Vitro Influenza Influenza A virus Influenza Therapeutic Integration Host Factors Lead Libraries Life Liver Microsomes Mediating Morbidity - disease rate Mutation National Institute of Allergy and Infectious Disease Oral Orthomyxoviridae Oseltamivir Permeability Pharmaceutical Preparations Phase Population Property Protein Isoforms Proteins Pyrimidine Pyrimidines RNA RNA Viruses Research Rimantadine Series Small Business Technology Transfer Research Structure Structure-Activity Relationship Therapeutic Toxic effect Vaccination Vaccines Viral Virulent Virus Virus Diseases Virus Inhibitors analog anti-influenza base clinical candidate cytotoxicity design drug development flu improved indexing influenza M2 influenza virus vaccine influenzavirus inhibitor/antagonist ion channel blocker mortality mouse model neutralizing antibody novel therapeutics pandemic disease pandemic influenza prophylactic protein H(3)resistant strain scaffold seasonal influenza small molecule small molecule inhibitor social tissue culture

项目摘要

Influenza A viruses belong to the Orthomyxoviridae family with a negative-sense, segmented RNA genome, which can cause seasonal or pandemic flu with high morbidity and significant mortality. Vaccination is the most prevalent prophylactic means for controlling influenza infections. However, an effective vaccine usually takes at least 6 months to develop for the circulating strains. Furthermore, vaccination has limited effectiveness in treatment of immunocompromised patients, and its effectiveness is also limited during a pandemic. The current therapeutic options for flu infections are all based on the NA inhibitors (NAIs), while the influenza M2 ion channel blockers (amantadine and rimantadine) are not recommended anymore since all the circulating influenza strains are resistant to them. However, the rapid emergence of the NAI-resistant strains of influenza A viruses strongly suggests that NAIs alone may not be sufficient as an effective means of the anti-flu therapies, and thus new treatment options targeting the other viral/host factors are urgently needed. This application defines a plan to develop potent, small molecule inhibitors, which block entry of influenza A viruses. We have identified compounds that inhibit entry of infectious influenza A viruses (IC50 values ≤1 µM). These hit compounds exhibit selectivity for H3N2 and H7N1 entry. The overall objective of this Phase I application is to develop these inhibitors as potential anti-flu therapeutics. This application will focus on the following three specific aims: (1) Synthesize structurally diverse analogs of the anti-flu CBS1193 hit series based on structure-activity relationships (SARs) to improve potency and selectivity. (2) Validateothe lead inhibitor candidates in the infectious assay and investigate the mechanism of action (MOA) of the inhibitors. (3) Select flu inhibitors with in vitro ADME properties suitable for i.v. and oral dosing.

甲型流感病毒属于正粘病毒科，具有负义，分段RNA基因组，可引起高发病率的季节性或大流行性流感和显着的死亡率。然而，有效的疫苗通常至少需要 6 次。此外，疫苗接种也有限。治疗免疫功能低下患者的有效性，其有效性也目前针对流感感染的治疗方案都是有限的。 NA抑制剂（NAIs），而流感M2离子通道阻滞剂（金刚烷胺）和金刚乙胺）不再推荐，因为所有正在流行的流感然而，NAI 抗性菌株迅速出现。流感病毒的数量强烈表明，单独的 NAI 可能不足以作为一种有效的治疗方法。抗流感治疗的有效手段，因此针对流感的新治疗方案迫切需要其他病毒/宿主因素。该应用程序定义了一个开发计划。我们拥有有效的小分子抑制剂，可以阻止甲型流感病毒的进入。鉴定出抑制传染性甲型流感病毒进入的化合物（IC50值≤1 µM）。这些命中化合物对 H3N2 和 H7N1 表现出选择性。第一阶段申请的目标是开发这些抑制剂作为潜在的抗流感药物该应用程序将重点关注以下三个具体目标：（1）合成抗流感 CBS1193 热门系列的结构多样的类似物 (2) 结构-活性关系（SAR）以提高效力和选择性。在感染性测定中验证先导抑制剂候选物并研究 (3) 用体外 ADME 选择流感抑制剂适合静脉注射和口服给药的特性。