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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

基本信息

批准号：
10772408
负责人：
Anthony WG Burgett
金额：
$ 3.32万
依托单位：
UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
依托单位国家：
美国
项目类别：
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/10772408
关键词：
2019-nCoV Alternative Splicing 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 Membrane Messenger RNA Mission Modality Modeling Morphology Nonsense-Mediated Decay Pathogenicity Pathway interactions Process Program Development Proliferating Proteins Public Health Publications Publishing RNA RNA Viruses RNA replication Reporting Repression Research Rhinovirus Role System Testing Therapeutic Therapeutic Intervention Translations United States National Institutes of Health Viral Viral Physiology Viral Proteins Virus Virus Diseases Virus Replication Work Zika Virus antiviral drug development antiviral immunity 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

项目摘要

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危机清楚地表明，有必要制定新的模式