Quinolizidines as Novel HIV-1 Entry Inhibitors

喹啉齐啶作为新型 HIV-1 进入抑制剂

• 批准号: 9322052
• 负责人: Chin-Ho Chen
• 金额: $ 44.43万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-17 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9322052
• 关键词: AIDS therapy; Acquired Immunodeficiency Syndrome; Animal Model; Anti-HIV Agents; Anti-Inflammatory Agents; Anti-Retroviral Agents; Anti-inflammatory; Biological; Computer Simulation; Development; Disease; Drug Design; Drug Kinetics; Drug Targeting; Drug resistance; Drug toxicity; Effectiveness; Evaluation; Future; Goals; HIV; HIV-1; In Vitro; Individual; Infection; Inflammation; Inflammatory; Lead; Life Cycle Stages; Molecular Mechanisms of Action; Natural Products; Photoaffinity Labels; Plants; Research Project Grants; Resistance; Structure-Activity Relationship; Testing; Toxic effect; Viral; Virus; Virus Replication; Work; analog; base; design; drug development; functional group; immune activation; improved; in vitro activity; in vivo; in vivo Model; inhibitor/antagonist; mouse model; mutant; novel; novel therapeutics; public health relevance; scaffold

 DESCRIPTION (provided by applicant): While anti-retroviral therapy (ART) is successful in controlling virus replication in HIV-1 positive individuals, the virus is suppressed rather than trly eradicated. Toxicity and drug resistance associated with long term ART remain to be a challenge for effective AIDS therapy. Thus, development of new therapeutics with novel mechanism of action may further improve current ART. Our long-term goal is to identify novel anti-HIV drugs that can eventually eradicate the virus in infected individuals. As a step toward this goal, we have identified a class of quinolizidines, including aloperine, which inhibit HIV at -5 uM by blocking the viral entry. Aloperine has been shown to have anti-inflammatory activity, which may also work to relieve immunopathogenesis associated with HIV-1 infection. Our preliminary structural optimization has yielded aloperine derivatives with approximately 10-fold increase in anti-HIV-1 activity. Based on these promising results, we hypothesize that more potent anti- HIV quinolizidines with anti-inflammatory activity can be obtained through rational drug design. The goal of this project is to improve the potency of aloperine and to establish the pharmacological profiles, such as mechanism of action and in vivo efficacy, which are essential for further drug development. The following Specific Aims will be carried out to test this hypothesis and achieve our goal in identifying promising anti-HIV agents: (1) to determine the molecular mechanisms of action of the anti-HIV-1 entry activity of quinolizidines. Our approach to achieve this aim includes photoaffinity labeling of the drug targets and characterization of HIV-1 mutants resistant to the quinolizidines; (2) to identify potent quinolizidine derivatives through lead optimization. Our approach to achieve this goal is to optimize both the functional groups and the quinolizidine scaffold to obtain derivatives with low nM anti-HIV-1 potency; (3) to establish the anti-HIV-1 profiles of aloperine derivatives using in vitro and in vivo models. Aloperine (MW=232) is a natural product found in several common plant species and can be obtained by total synthesis. Aloperine has been shown to have optimal PK profiles and to be effective in animal models of inflammatory diseases. Thus, it is an attractive hit for lead optimization. Upon completion of the proposed study, we expect to identify optimized aloperine derivatives with low nM potency and in vivo efficacy against HIV-1. In addition, this study will determine the potential beneficial anti-inflammatory effect of aloperine on immune activation associated with HIV-1 infection and establish structure-activity relationship profiles for future structural optimization for potent anti-inflammatory activity. Such compounds with the dual modes of action may become a useful addition to ART, and have potential to reduce inflammation associated with HIV-1 infection.

 描述(申请人提供)：虽然抗逆转录病毒疗法(ART)成功地控制了HIV-1阳性患者的病毒复制，但病毒被抑制而不是被彻底根除。与长期抗逆转录病毒治疗相关的毒性和耐药性仍然是有效治疗艾滋病的一个挑战。因此，开发具有新作用机制的新疗法可能会进一步改善当前的ART。我们的长期目标是找到新的抗艾滋病毒药物，最终可以根除感染者体内的病毒。作为实现这一目标的一步，我们已经确定了一类喹诺利定类药物，包括alopine，它们通过阻止病毒进入而在-5微米处抑制艾滋病毒。苦参碱已被证明具有抗炎活性，这也可能有助于缓解与HIV-1感染相关的免疫病理机制。我们的初步结构优化已经产生了苦豆碱衍生物，其抗HIV-1活性大约增加了10倍。基于这些有希望的结果，我们推测，通过合理的药物设计，可以获得更有效的具有抗炎活性的抗HIV药物。该项目的目标是提高苦豆碱的药效，并建立药理学特征，如作用机制和体内疗效，这对进一步的药物开发至关重要。为了验证这一假说，并实现我们在寻找有前景的抗HIV药物方面的目标，我们将进行以下具体目标：(1)确定喹诺利啶类药物抗HIV-1进入活性的分子机制。我们实现这一目标的方法包括光亲和标记药物靶标和表征HIV-1耐药突变株；(2)通过先导优化来鉴定有效的喹诺利定衍生物。我们实现这一目标的方法是优化官能团和喹诺利定支架，以获得低NM抗HIV-1效力的衍生物；(3)通过体外和体内模型建立苦豆碱衍生物的抗HIV-1谱。苦豆碱(MW=232)是一种天然产物，存在于几种常见植物中，可通过全合成获得。苦参碱已被证明具有最佳的PK谱，并在炎症性疾病的动物模型中有效。因此，对于Lead优化来说，它是一个有吸引力的热门产品。在这项拟议的研究完成后，我们预计将确定具有低NM效力和体内抗HIV-1效果的优化的苦豆碱衍生物。此外，本研究将确定苦豆碱在HIV-1感染相关的免疫激活中潜在的有益抗炎作用，并为未来有效抗炎活性的结构优化建立构效关系曲线。这种具有双重作用模式的化合物可能成为抗逆转录病毒治疗的有用添加剂，并有可能减少与艾滋病毒-1感染相关的炎症。