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: 8460830
• 负责人: JOSEPH G SODROSKI
• 金额: $ 4.24万
• 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 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8460830
• 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; 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; screening; 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（由申请人提供）：人类免疫缺陷病毒（HIV-1）是获得性免疫缺陷综合症（AIDS）的病原体。全球 HIV-1 大流行（约 3500 万人感染）每年新增感染人数为 2-300 万人。改变这一流行病的进程需要预防 HIV-1 传播，其中大部分是通过性行为传播的。在缺乏有效疫苗的情况下，迫切需要阻止 HIV-1 性传播的方式。最近，研究表明特定抗逆转录病毒药物的使用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物作为预防措施的普遍适用性。可用作局部杀菌剂的新型广泛活性抗病毒剂可以弥补这些缺陷。 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标。 HIV-1 包膜暴露在病毒表面，可被水溶性抑制剂接触，并且每个病毒颗粒上的数量很少。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。尽管已经鉴定出一些 HIV-1 进入抑制剂，但耐药 HIV-1 变异体要么自然存在，要么在治疗过程中形成。我们设计了一种筛选策略来识别新的广泛的 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。这种细胞-细胞融合测定和特异性控制测定将在 NIH 小分子库的初步筛选中并行使用。排名最高的化合物将通过二次筛选进行验证，评估重现性、剂量反应、广度和特异性。涉及具有多种 HIV-1 和其他逆转录病毒包膜糖蛋白的病毒的单轮复制的第三次测定可以以适度的通量进行，并将提供有关效力、广度和特异性的信息。评估作用机制的其他三级测定在 主要研究者的实验室，并将应用于选定的化合物。特异性和广泛的抑制剂将被修改以提高效力，同时保留广度。本研究中鉴定的化合物可能可用作预防性杀菌剂、治疗已感染个体以及作为了解 HIV-1 进入的复杂、多步骤过程的探针。