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（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征（AIDS）的病因学药。全球HIV-1大流行（感染约3500万人）每年受到200至300万种新感染。改变这种大流行的过程需要预防HIV-1传播，其中大多数发生性行为。在没有有效的疫苗的情况下，迫切需要阻止性HIV-1传播的方式。最近，已经研究了特定抗逆转录病毒药物的使用，并证明可以部分保护高危性伴侣免受HIV-1感染。但是，部分功效，药物副作用和抗药性病毒的出现限制了这些特定药物作为预防措施的一般适用性。可以用作局部杀菌剂的新的广泛活跃的抗病毒药物可以解决这些缺陷。介导病毒进入靶细胞的HIV-1包膜糖蛋白（ENVS）代表了这种预防剂的吸引力靶标。 HIV-1 Envs暴露在病毒表面上，可用于水溶性抑制剂，并且每个病毒座的数量很少。 ENV抑制剂被用作杀菌剂的抑制剂不必被宿主细胞系统地吸收或吸收，从而限制了潜在的毒性。 ENV的保守元素介导受体结合，构象变化和膜融合，为抑制提供了几种潜在的靶标。尽管已经鉴定出某些HIV-1进入抑制剂，但在治疗过程中自然存在抗药性HIV-1变体。我们制定了一种筛选策略，以鉴定HIV-1进入的新宽范围抑制剂。在我们的筛选测定中，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 - 细胞融合测定和特异性控制测定法将在NIH小分子库的主要屏幕中并行使用。排名最高的化合物将通过评估可重复性，剂量反应，广度和特异性的二级屏幕来验证。可以以适度的吞吐量进行涉及多个HIV-1和其他逆转录病毒包膜糖蛋白的病毒单转复制的第三次试验，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第三次试验在 首席研究员的实验室，并将应用于选定的化合物。将修改特定和宽范围的抑制剂，以提高效力，同时保持广度。在这项研究中鉴定出的化合物可能是预防性微生物，作为已经感染的个体的治疗方法，以及了解HIV-1进入HIV-1的复杂多步骤过程的探针。