Anibamine, a novel CCR5 antagonist as anti-HIV lead compound

Anibamine，一种新型 CCR5 拮抗剂，作为抗 HIV 先导化合物

• 批准号: 7554769
• 负责人: YAN ZHANG
• 金额: $ 20.31万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-13 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7554769
• 关键词: AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Affinity; Alkaloids; Anti-HIV Agents; Anti-Retroviral Agents; Antiviral Agents; Automobile Driving; Back; Binding; Binding Sites; Biochemical; Biological; Biological Assay; Biological Factors; CCR5 gene; CXCR4 gene; Cell membrane; Cells; Characteristics; Chemicals; Chemokine (C-C Motif) Receptor 5; Class; Communicable Diseases; Competitive Binding; Development; Docking; Drug Interactions; Evaluation; Goals; HIV; HIV Envelope Protein gp120; HIV Receptors; HIV-1; Homology Modeling; Human; Inhibitory Concentration 50; Laboratories; Lead; Life; Ligands; Methodology; Methods; Molecular; Molecular Conformation; Pathway interactions; Peptides; Pharmaceutical Chemistry; Pharmaceutical Preparations; Population; Protein Binding; Public Health; Quantitative Structure-Activity Relationship; Reagent; Reporting; Research; Research Design; Resistance; Route; Screening procedure; Series; Site; Skeleton; Testing; Therapeutic; Therapeutic Agents; Therapeutic Uses; Toxic effect; Treatment Efficacy; United States; Viral Envelope Proteins; Virus; analog; anibamine; base; biological research; chemical synthesis; chemokine receptor; chemotherapeutic agent; design; feeding; high throughput screening; next generation; novel; novel strategies; pandemic disease; pathogen; predictive modeling; programs; pyridine; receptor

DESCRIPTION (provided by applicant): The chemokine receptor CCR5 is one of the essential co-receptors for the HIV virus entry to host cells. The application of CCR5 antagonist in blocking the virus entry will provide a novel anti-HIV therapeutic pathway. The long-term goal of our project is to develop potential antagonist(s) of chemokine receptor CCR5 as novel anti-HIV agents. Anibamine is the first and only natural product that has been reported to have inhibition affinity to CCR5 at 1 micromole. The specific hypothesis of this exploratory/developmental project is that an antagonist of CCR5 with structural character of anibamine may have therapeutic potency as anti-HIV agents. We base that hypothesis on the following facts: First, this natural product provides a novel structural skeleton as CCR5 antagonist compared with all other known high-throughput screening observations. Second, the binding pocket study of anibamine in CCR5 homology model has shown some common features that may be shared by other reported CCR5 antagonists. Therefore, the chemical synthesis of anibamine and its analogs acting as CCR5 antagonist may lead to a brand new type of chemotherapeutic agent for the HIV/AIDS treatment. Based on these observations, the focus of this proposal is the synthesis of CCR5 non-peptide antagonists carrying structural features of anibamine. The specific aims are to (1) design and synthesize novel compounds as anibamine derivatives acting as novel CCR5 antagonists and (2) to evaluate the ligands synthesized for anti-HIV activity to develop the next generation lead compound. So far we have accomplished the total synthesis of anibamine by the exploration of multiple synthetic routes. We also have applied the homology model of CCR5 that we built to study the binding locus for anibamine and other known antagonists. A series of new ligands have been designed and their synthetic routes have been proposed based on our total synthesis results. This exploratory/developmental project will focus on the development of novel lead compound with the structural character of anibamine as the new anti-HIV agents. PUBLIC HEALTH RELEVANCE: The long-term goal of our project is to develop potential antagonist(s) of chemokine receptor CCR5 as anti-HIV/AIDS agents. This exploratory/developmental project will focus on the development of novel lead compound with the structural character of anibamine, the first and only natural product as CCR5 antagonist, as new anti-HIV agents. We believe it is urgent to pursue this study in order to identify new lead compounds as novel CCR5 antagonist, and to exploit the antiviral activity of these ligands.

描述（申请人提供）：趋化因子受体CCR5是HIV病毒进入宿主细胞的重要辅助受体之一。 CCR5拮抗剂在阻断病毒进入方面的应用将提供一条新的抗HIV治疗途径。我们项目的长期目标是开发趋化因子受体 CCR5 的潜在拮抗剂作为新型抗 HIV 药物。阿尼巴胺是第一个也是唯一一个被报道对 1 微摩尔 CCR5 具有抑制亲和力的天然产物。该探索/开发项目的具体假设是，具有阿尼巴胺结构特征的 CCR5 拮抗剂可能具有作为抗 HIV 药物的治疗效力。我们的假设基于以下事实：首先，与所有其他已知的高通量筛选观察结果相比，这种天然产物提供了作为 CCR5 拮抗剂的新颖结构骨架。其次，CCR5 同源模型中阿尼巴胺的结合口袋研究显示了其他报道的 CCR5 拮抗剂可能具有的一些共同特征。因此，化学合成阿尼巴胺及其类似物作为CCR5拮抗剂可能会产生一种用于治疗HIV/AIDS的全新化疗药物。基于这些观察，该提案的重点是合成具有阿尼巴胺结构特征的CCR5非肽拮抗剂。具体目标是 (1) 设计和合成作为新型 CCR5 拮抗剂的苯胺衍生物等新型化合物，以及 (2) 评估合成的配体的抗 HIV 活性，以开发下一代先导化合物。目前我们通过多条合成路线的探索，已经完成了苯胺的全合成。我们还应用了我们建立的 CCR5 同源模型来研究阿尼巴明和其他已知拮抗剂的结合位点。根据我们的全合成结果，设计了一系列新的配体并提出了它们的合成路线。该探索/开发项目将重点开发具有阿尼巴胺结构特征的新型先导化合物作为新型抗艾滋病毒药物。 公共健康相关性：我们项目的长期目标是开发趋化因子受体 CCR5 的潜在拮抗剂作为抗 HIV/AIDS 药物。该探索/开发项目将重点开发具有阿尼巴胺结构特征的新型先导化合物，这是第一个也是唯一一个作为 CCR5 拮抗剂的天然产物，作为新型抗 HIV 药物。我们认为迫切需要开展这项研究，以确定新的先导化合物作为新型 CCR5 拮抗剂，并利用这些配体的抗病毒活性。