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（由申请人提供）：趋化因子受体CCR5是HIV病毒进入宿主细胞的必不可少的共受体之一。 CCR5拮抗剂在阻断病毒进入中的应用将提供一种新型的抗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。芳基胺是据报道在1微米处对CCR5具有抑制亲和力的第一个也是唯一的天然产物。该探索性/发育项目的具体假设是，具有阳极胺结构特征的CCR5的拮抗剂可能具有治疗效力为抗HIV药物。我们以以下事实为基础：首先，与所有其他已知的高通量筛选观测值相比，这种天然产物作为CCR5拮抗剂提供了一种新型的结构骨架。其次，在CCR5同源性模型中，芳基胺的结合口袋研究显示了一些共同特征，这些特征可能由其他报道的CCR5拮抗剂共享。因此，阳极胺的化学合成及其作为CCR5拮抗剂的类似物可能会导致艾滋病毒/艾滋病治疗的全新化学治疗剂。基于这些观察结果，该提案的重点是携带Anibamine结构特征的CCR5非肽拮抗剂的合成。具体的目的是（1）设计和合成新型化合物作为充满新型CCR5拮抗剂的芳基胺衍生物，以及（2）评估抗HIV活性合成的配体以开发下一代铅化合物。到目前为止，我们已经通过探索多个合成途径来实现Anibamine的总合成。我们还应用了CCR5的同源模型，我们构建了该模型，以研究苯胺和其他已知拮抗剂的结合基因座。已经设计了一系列新的配体，并根据我们的总合成结果提出了它们的合成路线。这个探索性/发展项目将着重于新型铅化合物的发展，其结构特征是新的抗HIV剂。 公共卫生相关性：我们项目的长期目标是发展趋化因子受体CCR5作为抗HIV/艾滋病剂的潜在拮抗剂。这个探索性/发展项目将着重于具有新型铅化合物的发展，其结构特征是Anibamine（作为CCR5拮抗剂）作为新的抗HIV剂的第一批也是唯一的天然产物。我们认为，为了确定新的铅化合物为新的CCR5拮抗剂，并利用这些配体的抗病毒活性，我们迫切需要进行这项研究。