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，可能导致轻度至严重疾病， 有时会导致死亡。目前，神经氨酸酶（NA）抑制剂，Oseltamivir，Zanamivir和 peramivir是美国疾病预防症中建议使用的FDA批准的抗炎性病毒药物 最近循环流感病毒。但是，有许多不同的流感病毒亚型，它们不断 更改。与新兴的耐药性和与 抗FLU药物。因此，需要新颖有效的抗病毒剂来应对流感。长期 这项研究的目标是鉴定具有强大活性以控制流感的新型抗激素病毒剂 病毒感染。作为朝着这个目标迈出的一步，我们已经确定了一类喹啉类药物，例如丙吡啶， 抑制流感病毒的多种亚型，包括NA抑制剂抗性流感和B的CDC面板 在亚姆浓度下的病毒。靶向病毒核蛋白（NP）似乎是负责 喹啉苷的广泛抗炎性病毒活性。更重要的是，铅乙酰胺衍生物有效 使用鼠标模型在体内。通过这些有希望的结果，该研究项目的目标是改善 喹啉胺的效力并阐明其作用机理。工作的假设是 通过合理的药物设计，具有有效和宽阔的抗炎性病毒活性的喹啉衍生物可以是 获得。将实现两个具体目标来检验这一假设并实现我们的目标 有希望的抗激素病毒剂。目的1是通过结构提高喹啉苷的效力 修改。我们实现此目标的方法是优化喹啉的功能群体 获得具有低NM效力和最佳药理特征的衍生物。目标2是建立抗病毒 概况并阐明喹啉苷的作用机理。这个目标的目标包括 确定喹啉苷的药理概况和定义作用机理。 药理学评估将着重于确定抗病毒活性的广度和功效 小鼠模型中的喹啉定因衍生物。热门化合物Aloperine是一种具有独特的喹啉苷 适用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 其在溃疡性结肠炎和炎症细胞因子调节中的治疗作用的模型。我们的初步 铅优化工作已导致具有亚UM活性的衍生物。拟议研究的完成是 预计将产生新的抗FLU药物，以抑制广泛的流感病毒，包括病毒菌株 在低NM效力下，对当前CDC推荐的抗Influenza疗法具有抗性。