Aloperine derivatives as novel anti-influenza agents

作为新型抗流感药物的阿哌林衍生物

• 批准号: 9891004
• 负责人: Chin-Ho Chen
• 金额: $ 20.13万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-11 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9891004
• 关键词: Animal Model; Anti-influenza Agent; Antiviral Agents; Biological; Cell model; Centers for Disease Control and Prevention (U.S.); Cessation of life; Characteristics; Drug Design; Drug resistance; Effectiveness; Evaluation; Exhibits; FDA approved; Flu virus; Goals; HIV; HIV-1; Infection; Inflammatory; Influenza; Influenza A virus; Influenza B Virus; Influenza Therapeutic; Lead; Modification; Natural Products; Neuraminidase inhibitor; Nucleoproteins; Oseltamivir; Outcome Study; Pharmaceutical Preparations; Pharmacology; Phase II Clinical Trials; Pilot Projects; Property; Regulation; Reporting; Research; Research Project Grants; Resistance; Structure; Testing; Therapeutic; Therapeutic Effect; Time; Ulcerative Colitis; Viral; Virus Diseases; Virus Inhibitors; anti-influenza; anti-influenza drug; cytokine; drug candidate; drug development; drug resistant virus; flu activity; functional group; improved; in vitro activity; in vivo; influenzavirus; lead optimization; mouse model; novel; resistant strain; respiratory; scaffold; zanamivir

Influenza is a contagious respiratory illness caused by influenza virus, which can cause mild to severe illness, and at times can lead to death. Currently, the neuraminidase (NA) inhibitors, oseltamivir, zanamivir, and peramivir, are the FDA-approved anti-Influenza virus drugs recommended by the US CDC for use against recently circulating influenza viruses. However, there are many different flu virus subtypes and they are constantly changing. This is further compounded by emerging drug resistance and limited effectiveness associated with anti-flu drugs. Thus, novel and effective antiviral agents are needed to cope with influenza. The long-term goal of this study is to identify novel anti-influenza virus agents with potent and broad activity to control flu virus infection. As a step toward this goal, we have identified a class of quinolizidines, such as aloperine, that inhibit multiple subtypes of influenza viruses including a CDC panel of NA inhibitor resistant influenza A and B viruses at sub-uM concentrations. Targeting the viral nucleoprotein (NP) appears to be responsible for the broad anti-influenza virus activity of the quinolizidines. More importantly, a lead aloperine derivative is effective in vivo using a mouse model. With these promising results, the goal of this research project is to improve the potency of the quinolizidines and to elucidate their mechanism of action. The working hypothesis is that through rational drug design, quinolizidine derivatives with potent and broad anti-influenza virus activity can be obtained. Two Specific Aims will be carried out to test this hypothesis and achieve our goal in identifying promising anti-influenza virus agents. Aim 1 is to improve the potency of quinolizidines by structural modifications. Our approach to achieve this aim is to optimize the functional groups of the quinolizidines to obtain derivatives with low nM potency and optimal pharmacological profiles. Aim 2 is to establish the antiviral profiles and to elucidate the mechanism of action of the quinolizidines. The goal of this aim includes determining the pharmacological profiles and defining mechanisms of action of the quinolizidines. Pharmacological evaluation will focus on determining the breadth of antiviral activity and the efficacy of quinolizidine derivatives in a mouse model. The hit compound, aloperine, is a quinolizidine with unique physicochemical and biological properties suitable for lead optimization. It has been tested in cell and animal models for its therapeutic effects in ulcerative colitis and regulation of inflammatory cytokines. Our preliminary lead optimization efforts have resulted in derivatives with sub-uM activity. Completion of the proposed study is expected to yield new anti-flu agents that inhibit a broad spectrum of influenza viruses, including viral strains that are resistant to the current CDC recommended anti-influenza therapeutics, at low nM potency.

流感是一种由流感病毒引起的传染性呼吸道疾病，可导致轻度至重度疾病， 有时可能导致死亡。目前，神经氨酸酶（NA）抑制剂奥司他韦、扎那米韦和 帕拉米韦（peramivir）是FDA批准的抗流感病毒药物，美国疾病预防控制中心（CDC）推荐用于治疗流感病毒。 最近流行的流感病毒。然而，流感病毒有许多不同的亚型，并且不断变化。 改变。新兴的耐药性和与相关药物相关的有限有效性进一步加剧了这一问题 抗流感药物。因此，需要新型有效的抗病毒剂来应对流感。长期来看 这项研究的目标是确定具有有效和广泛活性的新型抗流感病毒药物来控制流感 病毒感染。作为实现这一目标的一步，我们已经确定了一类喹诺里西啶，例如苦豆碱， 抑制流感病毒的多种亚型，包括 CDC 小组对 NA 抑制剂具有抗性的甲型和乙型流感病毒 亚微米浓度的病毒。靶向病毒核蛋白（NP）似乎是导致 喹嗪类化合物具有广泛的抗流感病毒活性。更重要的是，先导苦豆碱衍生物是有效的 使用小鼠模型进行体内实验。有了这些有希望的结果，该研究项目的目标是提高 喹啉西啶的效力并阐明其作用机制。工作假设是 通过合理的药物设计，可以开发出具有强效、广泛的抗流感病毒活性的喹啉西啶衍生物。 获得。将执行两个具体目标来检验这一假设并实现我们的目标： 有前景的抗流感病毒药物。目标 1 是通过结构改进喹啉西啶的效力 修改。我们实现这一目标的方法是优化喹啉齐啶的官能团，以 获得具有低 nM 效力和最佳药理学特征的衍生物。目标2是建立抗病毒药物 概况并阐明喹啉西啶的作用机制。这一目标的目标包括 确定喹啉西啶的药理学特征并确定其作用机制。 药理学评价将侧重于确定抗病毒活性的广度和功效 小鼠模型中的喹啉西啶衍生物。热门化合物 aperine 是一种喹里西啶，具有独特的 适合先导化合物优化的理化和生物特性。已在细胞和动物中进行测试 其对溃疡性结肠炎的治疗作用和炎症细胞因子的调节模型。我们的初步 先导化合物优化工作已产生具有亚微米活性的衍生物。拟议研究的完成时间为 预计将产生新的抗流感药物，可抑制广谱流感病毒，包括病毒株 对当前 CDC 推荐的低 nM 效力的抗流感疗法具有耐药性。