Targeting the HIV RNA genome using fragment-based ligand discovery

使用基于片段的配体发现靶向 HIV RNA 基因组

• 批准号: 9346456
• 负责人: Katherine Deigan Warner
• 金额: $ 20.58万
• 依托单位: RIBOMETRIX, LLC
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-20 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9346456
• 关键词: Acquired Immunodeficiency Syndrome; Active Sites; Affinity; Antiviral Agents; Binding; Biological Assay; Biophysics; Cell Nucleus; Cessation of life; Chemicals; Chronic Disease; Clinical; Collaborations; Complex; Development; Drug Design; Drug Targeting; Elements; Ensure; Foundations; Generic Drugs; Genome; HIV; HIV Infections; HIV-1; Human; Infection; Lead; Libraries; Life; Ligands; Linezolid; Maps; Methods; Modeling; Monitor; Natural Products; Nuclear Export; Nucleotides; Pathogenicity; Patients; Pharmaceutical Chemistry; Pharmacologic Substance; Positioning Attribute; Process; Property; Proteins; RNA; RNA Binding; RNA Viruses; RNA analysis; Reaction; Regimen; Resolution; Response Elements; Ribosomal RNA; Sampling; Specificity; Structure; System; Technology; Testing; Therapeutic; Toxic effect; Untranslated RNA; Viral Load result; Virus; Virus Replication; Vision; base; drug discovery; experimental study; human disease; improved outcome; inhibitor/antagonist; innovative technologies; novel; novel therapeutics; prevent; rev Protein; screening; small molecule; small molecule inhibitor; small molecule therapeutics; standard of care; stem; structural biology; therapeutic development; therapeutic target; viral RNA; viral transmission

SUMMARY Once considered a death sentence, infection with HIV is now a manageable, chronic disease. To keep the viral load low and to prevent progression to AIDS, patients are required to adhere to a regime of multiple antivirals for life. Long-term treatment does not eliminate the virus and can lead to serious toxicities. Therapies that either cure infection or that offer improvements in convenience or tolerability are needed. Current anti-HIV therapeutics target fewer than half a dozen protein active sites. Significant recent advances in the structural biology of HIV offer an opportunity to develop therapeutics that target tertiary structures within the HIV RNA genome that are essential to the viral replication cycle. RNA is a compelling target for small-molecule drug discovery, and the genomes of RNA viruses, such as HIV, contain highly conserved targetable structures. Multiple natural products target ribosomal RNA, establishing proof of concept for RNA as a drug target; however, RNA-targeted drug discovery remains a nascent field. Specific tertiary structures in the HIV RNA genome are essential for viral replication, and we are ideally positioned to develop a screening system for small molecules that bind to these tertiary structure elements. The well-characterized Rev response element (RRE) forms a complex with Rev protein that is essential for export of HIV RNAs from the nucleus, a process necessary for productive infection. We will employ the Ribometrix lead discovery platform to identify small molecules with favorable medicinal chemistry properties that bind to the RRE to block binding of Rev or to disrupt the tertiary structure recognized by Rev. These leads will serve as a foundation for development of novel anti-HIV therapeutics. At Ribometrix, our lead discovery platform combines SHAPE-MaP, a high-quality, rigorous biophysical technology for RNA structure analysis, and fragment-based drug discovery (FBDD), a well-validated strategy for lead compound identification that allows efficient sampling of chemical space. The strategy we propose to develop here can be used in efforts to identify small molecules that bind to and disrupt structures of diverse therapeutically important RNAs. Thus, we are poised to fully test and establish proof-of-principle for an efficient and generic approach for RNA-targeted ligand discovery, focused on a critical step of the HIV replication cycle.

摘要 曾经被认为是死刑的艾滋病毒感染，现在是一种可控的慢性病。为了保持 病毒载量低，并防止进展为艾滋病，患者被要求坚持多重 终生的抗病毒药物。长期治疗并不能消除病毒，还可能导致严重的毒性。 要么治愈感染，要么改善方便性或耐受性的疗法是必要的。 目前的抗艾滋病毒治疗药物针对的蛋白质活性部位不到六个。近期取得的重大进展 在艾滋病毒的结构生物学中提供了一个机会来开发针对三级结构的疗法 对病毒复制周期至关重要的HIV RNA基因组。 RNA是小分子药物发现的一个引人注目的目标，而RNA病毒的基因组，如艾滋病毒， 含有高度保守的靶向结构。多种天然产物靶向核糖体RNA，建立 核糖核酸作为药物靶点的概念证明；然而，针对核糖核酸的药物发现仍然是一个新领域。 HIV RNA基因组中特定的三级结构对于病毒复制是必不可少的，我们理想的情况是 定位于开发与这些三级结构元素结合的小分子的筛选系统。 特性良好的REV反应元件(RRE)与REV蛋白形成复合体，这是 从细胞核输出艾滋病毒RNA，这是生产性感染所必需的过程。我们将采用 Ribometrix先导发现平台用于鉴定具有良好药物化学性质的小分子 与RRE结合以阻止REV的结合或破坏REV识别的三级结构 将作为开发新的抗艾滋病毒疗法的基础。 在Ribometrix，我们领先的发现平台结合了SHAPE-MAP，一种高质量、严谨的生物物理 RNA结构分析技术和基于片段的药物发现(FBDD)，这是一种经过充分验证的策略 用于铅化合物鉴定，允许对化学空间进行有效采样。我们提出的战略是 在此开发可用于鉴定结合和破坏不同结构的小分子 具有重要治疗作用的RNA。因此，我们准备全面测试并建立一个 高效和通用的RNA靶向配体发现方法，专注于HIV的关键步骤 复制周期。