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，可导致轻度至重度疾病， 有时会导致死亡目前，神经氨酸酶（NA）抑制剂奥司他韦、扎那米韦和 帕拉米韦是FDA批准的抗流感病毒药物，由美国CDC推荐用于对抗 最近流行的流感病毒。然而，有许多不同的流感病毒亚型，他们不断 改变这进一步加剧了新出现的耐药性和有限的有效性相关的 抗流感药物因此，需要新的和有效的抗病毒剂来科普流感。长期 本研究的目的是鉴定新型抗流感病毒药物，这些药物具有有效和广泛的控制流感的活性 病毒感染。作为实现这一目标的一步，我们已经鉴定了一类喹嗪，如苦豆碱， 抑制流感病毒多种亚型，包括NA抑制剂抗性流感A和B的CDC组 浓度低于μ M的病毒。靶向病毒核蛋白（NP）似乎是负责 喹嗪类化合物具有广泛的抗流感病毒活性。更重要的是，铅苦豆碱衍生物是有效的 在体内使用小鼠模型。有了这些有希望的结果，本研究项目的目标是改善 喹嗪的效力，并阐明其作用机制。工作假设是， 通过合理的药物设计，具有强效和广谱抗流感病毒活性的喹里西啶衍生物， 得到了为了验证这一假设，并实现我们的目标，将进行两个具体的目标， 有前途的抗流感病毒剂。目的1是通过结构修饰提高喹嗪类药物的药效 修改.我们实现这一目标的方法是优化喹嗪的官能团， 获得具有低nM效力和最佳药理学特性的衍生物。目的二是建立抗病毒的 谱，并阐明喹嗪的作用机制。这一目标的目标包括 确定喹嗪类药物的药理学特征和确定其作用机制。 药理学评价将侧重于确定抗病毒活性的广度和 喹嗪啶衍生物在小鼠模型中的应用。热门化合物aloperine是一种喹嗪啶， 适合于铅优化的物理化学和生物学性质。它已在细胞和动物中进行了测试 在溃疡性结肠炎中的治疗作用和炎症细胞因子的调节的模型。我们的初步 先导优化努力已经产生了具有亚μ M活性的衍生物。拟议研究的完成时间为 有望产生新的抗流感药物，抑制广谱流感病毒，包括病毒株 对当前CDC推荐的抗流感治疗剂具有抗性的低nM效力的病毒。