Cellular Mechanism of Oxysterol-Binding Protein (OSBP) in Viral Proliferation: A Chemical Biology Approach

氧甾醇结合蛋白 (OSBP) 在病毒增殖中的细胞机制：化学生物学方法

• 批准号: 10212013
• 负责人: Anthony WG Burgett
• 金额: $ 41.69万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-08 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10212013
• 关键词: 2019-nCoV; Alternative Splicing; Antiviral Agents; Antiviral Response; Autophagocytosis; Biological; Biology; COVID-19 pandemic; Cell physiology; Cells; Cellular biology; Chemicals; Complex; Coronavirus; Coronavirus Infections; Dengue Virus; Disease; Dose; Drug Targeting; Enterovirus; Eukaryotic Cell; Family; Family Picornaviridae; Flavivirus; Foundations; Future; Generations; Goals; Hepatitis C; Human; Individual; Infection; Innate Immune Response; Lipids; Mediating; Mediator of activation protein; Membrane; Messenger RNA; Mission; Modality; Modeling; Morphology; Nonsense-Mediated Decay; Pathogenicity; Pathway interactions; Process; Program Development; Proteins; Public Health; Publications; Publishing; RNA; RNA Viruses; RNA replication; Reporting; Repression; Research; Rhinovirus; Role; Structure; System; Testing; Therapeutic; Therapeutic Intervention; Translations; United States National Institutes of Health; Viral; Viral Proteins; Virus; Virus Diseases; Virus Replication; Work; Zika Virus; antiviral immunity; base; cholesterol-binding protein; design; disability; drug development; human pathogen; insight; mortality; nanomolar; novel virus; oxysterol binding protein; pathogenic virus; prophylactic; protein function; response; sensor; small molecule; therapeutic lead compound

The current COVID-19 crisis starkly illustrates the need to develop new modalities for the therapeutic treatment of pathogenic single-stranded RNA (ssRNA) viruses, including against novel viruses that have yet to emerge. Human oxysterol-binding protein (OSBP) has recently been determined to be a critical mediator in the replication of a broad spectrum of ssRNA viral human pathogens, including the enteroviruses, rhinovirus, hepatitis C, Zika virus, Dengue fever viruses, and coronaviruses. OSBP is an ER-located, non-enzymatic protein reported to function as an important lipid sensor and lipid transporter in eukaryotic cells. Published research, including our own recent publications, has established the antiviral activity of structurally-diverse OSBP- targeting small molecules against multiple RNA pathogenic viruses. These discoveries present the opportunity for a paradigm shift in antiviral drug development: potentially drug targeting a human host protein, OSBP, that is required for viral proliferation of a broad-spectrum of RNA viruses, as opposed to targeting viral proteins present in individual viruses. We have discovered that transient, low dose treatment with the OSBP-targeting compound OSW-1-compound induces a longterm, multigenerational repression of OSBP, and the cells with repressed OSBP show a pronounced inhibition of ssRNA viral replication. Our preliminary results show that the OSW-1- compound has prophylactic antiviral activity at low nanomolar concentrations against several ssRNA viruses, including against one coronavirus tested. The longterm repression of OSBP, triggered by OSW-1, has no effect on cellular division, viability, or morphology. The purpose of this proposal is to understand the cellular role of OSBP in innate antiviral response. Our preliminary results show that OSBP: 1) regulates mTORC1 activity, 2) induces autophagy; 3) slows global protein translation; and 4) activates alternative splicing nonsense- mediated decay (AS-NMD) process, which is an RNA regulatory process. All of these OSBP- involved cellular processes would limit ssRNA viral replication individually, but there is little insight into the organization of these systems to establish a coordinated antiviral response.Our overall hypothesis is that OSBP serves in a major regulatory role to coordinate a multifaceted innate antiviral response to ssRNA infection. We propose a complete model of how OSBP senses early- stage viral infection and then triggers a multisystem response to block viral replication in cells, including through modulating mTOR1C activity and the AS-NMD system.

当前的Covid-19危机明显地说明了为发展新方式的必要性 致病性单链RNA（SSRNA）病毒的治疗治疗，包括针对 尚未出现的新型病毒。人氧蛋白酶结合蛋白（OSBP）最近具有 被确定为复制ssRNA病毒的关键介体 人类病原体，包括肠病毒，鼻病毒，肝炎，寨卡病毒，登革热。 病毒和冠状病毒。 OSBP是一种据报道功能的非酶级别的非酶蛋白 作为真核细胞中重要的脂质传感器和脂质转运蛋白。发表的研究，包括 我们自己最近的出版物已经建立了结构多样性OSBP-的抗病毒活动 针对多种RNA致病病毒的小分子。这些发现存在 抗病毒药物开发范式转变的机会：靶向A的药物 人类宿主蛋白OSBP，这是广泛的RNA的病毒增殖所必需的 病毒，而不是靶向单个病毒中存在的病毒蛋白。我们发现了 使用OSBP靶向化合物OSW-1-Compound的瞬时，低剂量处理可引起 长期对OSBP的多代抑制作用，而被抑制OSBP的细胞显示出 明显抑制ssRNA病毒复制。我们的初步结果表明OSW-1- 化合物在低纳摩尔浓度下具有预防性抗病毒活性相对于几个 ssRNA病毒，包括针对一个测试的冠状病毒。 OSBP的长期镇压， 由OSW-1触发，对细胞分裂，活力或形态没有影响。 该提案的目的是了解OSBP在先天抗病毒中的细胞作用 回复。我们的初步结果表明OSBP：1）调节MTORC1活动，2）诱导 自噬； 3）减慢全球蛋白质翻译； 4）激活替代剪接废话 - 介导的衰减（AS-NMD）过程，这是RNA调节过程。所有这些OSBP- 涉及的蜂窝过程将分别限制SSRNA病毒复制，但几乎没有洞察力 进入这些系统的组织以建立协调的抗病毒反应。 假设是OSBP担任主要调节作用，以协调多方面的先天性 抗病毒对SSRNA感染的反应。我们提出了一个完整的模型，说明OSBP如何早期感觉到 阶段病毒感染，然后触发对阻断细胞病毒复制的多系统反应， 包括通过调节MTOR1C活动和AS-NMD系统。