Broad-range Inhibitors of Human Immunodeficiency Virus Entry

人类免疫缺陷病毒进入的广泛抑制剂

• 批准号: 8327385
• 负责人: JOSEPH G SODROSKI
• 金额: $ 4.38万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8327385
• 关键词: Acquired Immunodeficiency Syndrome; Adverse drug effect; Anti-Retroviral Agents; Antiviral Agents; Binding; Biological; Biological Assay; CCR5 gene; CD4 Antigens; CXCR4 Receptors; Cell Line; Cell fusion; Cell membrane; Cell surface; Cells; Collaborations; Complex; Dose; Drug Formulations; Drug resistance; Drug toxicity; Elements; Epidemic; Exhibits; Firefly Luciferases; Genbank; Glycoproteins; Goals; HIV; HIV Envelope Protein gp120; HIV-1; Individual; Infection; Infection prevention; Laboratories; Local Microbicides; Measures; Mediating; Membrane Fusion; Modality; Monitor; Murine leukemia virus; Persons; Pharmaceutical Preparations; Prevention; Principal Investigator; Process; Prophylactic treatment; Proteins; Recombinants; Regimen; Reproducibility; Research; Retroviridae; Risk; Screening procedure; Sexual Partners; Sexual Transmission; Specificity; Structure; Structure-Activity Relationship; Surface; Testing; Toxic effect; United States National Institutes of Health; Vaccines; Variant; Viral; Virion; Virus; Virus Receptors; Virus Replication; Water; base; conformational conversion; counterscreen; cytotoxic; drug resistant virus; env Gene Products; env Glycoproteins; high throughput screening; improved; inhibitor/antagonist; lymphoblast; microbicide; pandemic disease; prevent; promoter; prophylactic; receptor; receptor binding; response; small molecule; small molecule libraries; transmission process

DESCRIPTION (provided by applicant): Human immunodeficiency virus (HIV-1) is the etiologic agent of acquired immunodeficiency syndrome (AIDS). The global HIV-1 pandemic (~35 million people infected) is sustained by 2-3 million new infections annually. Changing the course of this pandemic requires prevention of HIV-1 transmission, most of which occurs sexually. In the absence of an effective vaccine, modalities that block sexual HIV-1 transmission are desperately needed. Recently, the use of specific antiretroviral drugs has been investigated and shown to partially protect at-risk sex partners from HIV-1 infection. However, partial efficacy, drug side effects and the emergence of drug-resistant viruses limit the general applicability of these particular agents as prophylactic measures. New broadly active antiviral agents that can be used as topical microbicides could remedy these deficiencies. The HIV-1 envelope glycoproteins (Envs), which mediate virus entry into target cells, represent attractive targets for such prophylactic agents. The HIV-1 Envs are exposed on the viral surface, are accessible to water-soluble inhibitors and are present in low numbers on each virion. Env inhibitors used as microbicides need not be systemically absorbed or taken up by host cells, limiting potential toxicity. Conserved elements of Env mediate receptor binding, conformational changes, and membrane fusion, providing several potential targets for inhibition. Although some HIV-1 entry inhibitors have been identified, drug-resistant HIV-1 variants either exist naturally o develop during treatment. We have devised a screening strategy to identify new broad-range inhibitors of HIV-1 entry. In our screening assay, HIV-1 Env function leads to the fusion of Env-expressing cells with cells expressing the viral receptors. This cell-cell fusion assay and a specificity control assay will be used in parallel in a primary screen of the NIH small-molecule library. The highest-ranked compounds will be validated by a secondary screen that assesses reproducibility, dose-response, breadth and specificity. Tertiary assays involving single-round replication of viruses with multiple HIV-1 and other retroviral envelope glycoproteins can be performed at modest throughput and will provide information on potency, breadth and specificity. Additional tertiary assays to evaluate mechanism of action are well-established in the principal investigator's laboratory, and will be applied to selected compounds. Specific and broad-range inhibitors will be modified to improve potency while retaining breadth. The compounds identified in this study could potentially be useful as prophylactic microbicides, as treatments for already infected individuals, and as probes to understand the complex, multi-step process of HIV-1 entry.

描述（申请人提供）：人类免疫缺陷病毒（HIV-1）是获得性免疫缺陷综合征（AIDS）的病原体。全球HIV-1大流行（约3500万人感染）每年有200万至300万新感染者。要改变这一流行病的发展趋势，就必须预防艾滋病毒-1的传播，其中大多数是通过性行为传播的。在缺乏有效疫苗的情况下，迫切需要阻断HIV-1性传播的方法。最近，对使用特定抗逆转录病毒药物进行了调查，结果表明，这种药物可以部分保护高危性伴侣免受HIV-1感染。然而，部分功效、药物副作用和耐药病毒的出现限制了这些特定药剂作为预防措施的普遍适用性。新的广泛活性的抗病毒药物，可用作局部杀微生物剂可以弥补这些不足。HIV-1包膜糖蛋白（Envs）介导病毒进入靶细胞，是此类预防剂的有吸引力的靶点。HIV-1 Env暴露在病毒表面，可接触水溶性抑制剂，并且在每个病毒体上以低数量存在。用作杀微生物剂的Env抑制剂不需要被宿主细胞全身吸收或摄取，从而限制了潜在的毒性。Env的保守元件介导受体结合、构象变化和膜融合，提供了几个潜在的抑制靶点。虽然已经鉴定出一些HIV-1进入抑制剂，但耐药HIV-1变体要么自然存在，要么在治疗期间发展。我们设计了一种筛选策略，以确定新的广泛的HIV-1进入抑制剂。在我们的筛选试验中，HIV-1 Env功能导致表达Env的细胞与表达病毒受体的细胞融合。该细胞-细胞融合试验和特异性对照试验将平行用于NIH小分子文库的初步筛选。将通过评估重现性、剂量反应、广度和特异性的二次筛选来验证排名最高的化合物。三级检测涉及病毒与多种HIV-1和其他逆转录病毒包膜糖蛋白的单轮复制，可以在中等通量下进行，并将提供有关效价、广度和特异性的信息。用于评价作用机制的其他三级测定法已在临床试验中得到充分确立。 主要研究者的实验室，并将适用于选定的化合物。特异性和广谱抑制剂将被修改，以提高效力，同时保留广度。在这项研究中确定的化合物可能是有用的预防性杀微生物剂，作为治疗已经感染的个人，并作为探针，以了解复杂的，多步骤的过程中的HIV-1进入。