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（由申请人提供）：虽然抗逆转录病毒疗法（ART）成功地控制了HIV-1阳性个体中的病毒复制，但病毒是被抑制而不是真正根除的。与长期ART相关的毒性和耐药性仍然是有效治疗艾滋病的挑战。因此，开发具有新作用机制的新疗法可能会进一步改善目前的ART。我们的长期目标是确定新的抗HIV药物，最终可以根除感染个体中的病毒。作为实现这一目标的一步，我们已经鉴定了一类喹嗪类药物，包括苦豆碱，其通过阻断病毒进入而在约5 μ M时抑制HIV。Aloperine已被证明具有抗炎活性，这也可能有助于缓解与HIV-1感染相关的免疫发病机制。我们的初步结构优化产生了aloperine衍生物，抗HIV-1活性增加约10倍。基于这些有希望的结果，我们假设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喹嗪类药物。本项目的目标是提高苦豆碱的效力，并建立药理学特征，如作用机制和体内功效，这对于进一步药物开发至关重要。本论文的主要目的是：（1）确定喹嗪类化合物抗HIV-1进入活性的分子作用机制。我们实现这一目标的方法包括药物靶点的光亲和标记和对喹嗪类药物耐药的HIV-1突变体的表征;（2）通过先导化合物优化鉴定有效的喹嗪类衍生物。我们实现这一目标的方法是优化功能基团和喹嗪啶支架，以获得具有低nM抗HIV-1效力的衍生物;（3）使用体外和体内模型建立苦豆碱衍生物的抗HIV-1特性。苦豆碱（MW=232）是一种存在于几种常见植物中的天然产物，可以通过全合成获得。已显示Aloperine具有最佳PK特征，并且在炎性疾病的动物模型中有效。因此，这是一个有吸引力的命中铅优化.在完成拟议的研究后，我们期望鉴定出具有低nM效力和体内抗HIV-1功效的优化苦豆碱衍生物。此外，本研究将确定苦豆碱对与HIV-1感染相关的免疫激活的潜在有益抗炎作用，并建立结构-活性关系谱，用于未来强效抗炎活性的结构优化。这种具有双重作用模式的化合物可能成为ART的有用补充，并有可能减少与HIV-1感染相关的炎症。