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.

流感是由流感病毒引起的一种传染性呼吸道疾病，可以导致轻微到严重的疾病， 有时还会导致死亡。目前，神经氨酸酶(NA)抑制剂奥司他韦、扎那米韦和 帕拉米韦，是美国疾控中心推荐使用的FDA批准的抗流感病毒药物 最近流行的流感病毒。然而，有许多不同的流感病毒亚型，它们不断地 不断变化。新出现的耐药性和与以下疾病相关的有限效力进一步加剧了这种情况 抗流感药物。因此，需要新的有效的抗病毒药物来应对流感。长期的 这项研究的目的是寻找新的抗流感病毒药物，具有有效和广泛的控制流感活性 病毒感染。作为迈向这一目标的一步，我们已经确定了一类喹诺利定类药物，如alopine，它可以 抑制多种亚型流感病毒，包括抗甲型流感和乙型流感的NA抑制剂CDC小组 亚微米浓度的病毒。靶向病毒核蛋白(NP)似乎是导致 广谱的抗流感病毒活性的喹唑烷类化合物。更重要的是，先导苦豆碱衍生物是有效的。 在活体中使用小鼠模型。有了这些有希望的结果，本研究项目的目标是改善 目的：研究喹诺利定类药物的药效，并阐明其作用机制。工作假说是 通过合理的药物设计，可以开发出具有较强广谱抗流感病毒活性的喹诺利定衍生物。 获得。我们将通过两个具体的目标来检验这一假说，并实现我们在识别 前景看好的抗流感病毒药物。目的1是通过结构分析来提高喹诺利定类药物的效力。 修改。我们实现这一目标的方法是优化喹诺利定类化合物的官能团以 获得低NM效力和最佳药理特性的衍生物。目标2是建立抗病毒药物 并阐明喹诺利定类药物的作用机制。这一目标的目标包括 确定喹诺利定类药物的药理特性并确定其作用机制。 药理学评估将侧重于确定抗病毒活性的广度和疗效 小鼠模型中的喹诺利定衍生物。最受欢迎的化合物，alopine，是一种喹诺利定，具有独特的 适合于铅优化的物理化学和生物学特性。它已经在细胞和动物中进行了测试。 其治疗溃疡性结肠炎的模型及炎性细胞因子的调节。我们的预赛 领先的优化努力已导致衍生产品具有亚微米活性。建议研究的完成日期为 有望生产出新的抗流感药物，抑制包括病毒株在内的多种流感病毒 对目前疾控中心推荐的低NM效力的抗流感药物具有抵抗力。