Small Molecule HIV-1 Entry Inhibitor with Novel Mechanisms of Action

具有新颖作用机制的小分子 HIV-1 进入抑制剂

基本信息

批准号：
9884724
负责人：
Chin-Ho Chen
金额：
$ 41.83万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-01 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9884724
关键词：
AIDS therapy Animal Model Anti-HIV Agents Anti-Inflammatory Agents Anti-Retroviral Agents Antibodies Antiviral Agents Binding Biological Clinical Trials Disease Drug Binding Site Drug Design Drug Kinetics Drug resistance Drug toxicity Effectiveness Evaluation Exhibits Future Goals HIV HIV Entry Inhibitors HIV Envelope Protein gp120 HIV-1 Individual Infection Inflammation Inflammatory Lead Life Cycle Stages Mediating Membrane Fusion Molecular Mechanisms of Action Natural Products Pathogenesis Pharmacology Phase Photoaffinity Labels Plants Property Proteins Research Research Project Grants Structure Structure-Activity Relationship Testing Toxic effect Viral Virus Virus Replication Work analog animal efficacy antiretroviral therapy base design drug candidate drug development drug discovery drug resistant virus efficacy study functional group improved in silico inhibitor/antagonist lead optimization neutralizing antibody novel novel therapeutics preclinical development scaffold small molecule synergism

项目摘要

While anti-retroviral therapy (ART) can successfully control virus replication in HIV-1-positive individuals, the virus is suppressed rather than truly eradicated. Furthermore, toxicity and drug resistance associated with long- term ART remain a significant challenge for effective AIDS therapy. Thus, there is a need to develop new therapeutics with novel mechanisms of action to improve current ART. As a step toward developing novel anti- HIV agents, we have identified a class of quinolizidines, including aloperine, which inhibit HIV at 1-5 uM by blocking viral entry. Aloperine has been shown to exhibit anti-inflammatory properties, which could potentially be beneficial for relieving immunopathogenesis associated with HIV-1 infection. Our preliminary structural optimization has yielded aloperine derivatives with approximately 15-fold increase in anti-HIV-1 activity. Our mechanism of action study reveals that the V1/V2 loop of gp120, which is the target of several broad and potent neutralizing antibodies, is a critical determinant of the anti-entry activity of a current lead aloperine derivative. Based on these promising results, we hypothesize that potent anti-HIV quinolizidines can be obtained through rational drug design and become anti-HIV-1 drug candidates with novel mechanisms of action. The goal of this research project is to improve the anti-HIV potency of aloperine derivatives and determine their pharmacological profiles, such as mechanism of action and the breadth of anti-HIV activity, 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 entry inhibitors: 1) to elucidate the molecular mechanisms of action of the anti- HIV-1 entry activity of quinolizidines; 2) to identify potent quinolizidine derivatives through lead optimization; 3) to establish the anti-HIV-1 profiles of aloperine derivatives. 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. Such compounds with the dual modes of action may become a useful addition to ART, and have potential to reduce inflammation associated with persistent HIV-1 infection. We plan to complete the study in three years to reach the following milestones: a) obtaining aloperine derivatives with low nM potency, b) elucidating a novel mechanism of how these compounds inhibit HIV-1 entry, and c) identifying aloperine derivatives that exhibiting cross clade anti-HIV-1 activity and optimal pharmacokinetic profiles. Completion of the work in this proposal will yield highly promising anti-HIV1 agents and is critical for their further preclinical development including animal efficacy studies and optimization of their anti-inflammatory activity.

虽然抗逆转录病毒疗法 (ART) 可以成功控制 HIV-1 阳性个体中的病毒复制，但病毒被抑制而不是被真正消灭。此外，与长期相关的毒性和耐药性术语 ART 仍然是有效艾滋病治疗的重大挑战。因此，需要开发新的具有新颖作用机制的疗法可改善当前的 ART。作为开发新型抗病毒药物的一步 HIV 药物，我们已经鉴定出一类喹诺里西啶类药物，包括苦豆碱，它可以通过 1-5 uM 抑制 HIV 阻断病毒进入。 Aloperine 已被证明具有抗炎特性，这可能是有益于缓解与 HIV-1 感染相关的免疫发病机制。我们的初步架构优化产生了苦豆碱衍生物，其抗 HIV-1 活性增加了约 15 倍。我们的作用机制研究表明，gp120 的 V1/V2 环是多种广泛且有效的靶点中和抗体是目前领先的苦豆碱衍生物的抗进入活性的关键决定因素。基于这些有希望的结果，我们假设可以通过以下方式获得有效的抗 HIV 喹嗪类药物：合理的药物设计，成为具有新颖作用机制的抗HIV-1候选药物。此举的目标研究项目是提高苦豆素衍生物的抗艾滋病毒效力并确定其药理作用概况，例如作用机制和抗 HIV 活性的广度，这对于进一步药物治疗至关重要发展。将执行以下具体目标来检验这一假设并实现我们的目标识别有前景的抗 HIV 进入抑制剂：1）阐明抗 HIV 进入抑制剂的分子作用机制。喹嗪类药物的 HIV-1 进入活性； 2) 通过先导化合物优化鉴定有效的喹啉西啶衍生物； 3）建立苦豆素衍生物的抗 HIV-1 谱。 Aloperine (MW=232) 是一种天然产物，存在于几种常见的植物种类，可以通过全合成获得。 Aloperine 已被证明具有最佳 PK 曲线并在炎症性疾病动物模型中有效。因此，它对铅来说是一个有吸引力的打击优化。此类具有双重作用模式的化合物可能成为 ART 的有用补充，并且具有具有减少与持续 HIV-1 感染相关的炎症的潜力。我们计划在三年内达到以下里程碑：a) 获得低纳米效力的苦豆碱衍生物，b) 阐明这些化合物如何抑制 HIV-1 进入的新机制，以及 c) 鉴定苦豆碱具有跨进化枝抗 HIV-1 活性和最佳药代动力学特征的衍生物。完成该提案中的工作将产生非常有前途的抗 HIV1 药物，并且对其进一步的临床前研究至关重要开发包括动物功效研究和抗炎活性的优化。