Preclinical studies to establish the combination of apoA-I mimetic peptides and statins as novel therapy for COVID-19

建立 apoA-I 模拟肽和他汀类药物组合作为 COVID-19 新疗法的临床前研究

• 批准号: 10456506
• 负责人: Theodoros Kelesidis
• 金额: $ 33.54万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10456506
• 关键词: 2019-nCoV; Address; Aging; Air; Animals; Anti-Inflammatory Agents; Antiinflammatory Effect; Antioxidants; Antiviral Agents; Apolipoprotein A-I; Atherosclerosis; Attenuated; Blood Vessels; COVID-19; COVID-19 morbidity; COVID-19 pandemic; COVID-19 patient; COVID-19 treatment; Cardiovascular Diseases; Cell Line; Cells; Chronic; Clinical; Clinical Trials; Complement; Coronavirus Infections; Development; Endothelial Cells; Epithelial Cells; Formulation; Funding Opportunities; Future; Goals; HIV-1; Human; Immune response; Immunology procedure; Infection; Inflammation; Inflammatory; Inflammatory Response; Intervention; Lipids; Liquid substance; Long COVID; Lung; Membrane; Mitochondria; Modeling; Morbidity - disease rate; Oral; Oxidation-Reduction; Oxidative Stress; Parents; Pathway interactions; Peripheral Blood Mononuclear Cell; Prophylactic treatment; Proteins; Public Health; Reactive Oxygen Species; Research Methodology; Risk; SARS-CoV-2 inhibitor; Severities; Therapeutic; Therapeutic Effect; Tissues; Toll-like receptors; Toxic effect; Vaccines; Vascular Diseases; Vascular Endothelial Cell; Viral; Virus; Virus Diseases; Virus Replication; Work; aged; airway epithelium; atherogenesis; atorvastatin; attenuation; comorbidity; high risk population; in vivo; innovation; lung injury; macrophage; mimetics; mutant; novel; novel therapeutic intervention; novel therapeutics; peptidomimetics; preclinical study; resistant strain; response; severe COVID-19; therapeutic target; vascular inflammation

PROJECT SUMMARY/ABSTRACT The SARS-CoV-2 pandemic emphasizes the urgent need to determine pathways that can be targeted by novel antivirals. This proposal describes the use of the combination of apoA-I mimetics with statins as novel therapy for COVID-19. SARS-CoV-2 utilizes mitochondria to replicate in lung epithelial cells. Mitochondrial reactive oxygen species (mito-ROS) induce alterations of lipids, membranes and redox sensitive proteins and ultimately viral replication. Thus, we hypothesized that the antioxidant ApoA-I mimetic peptide 4F, that targets lipids, mito-ROS and redox pathways, has antiviral activity against SARS-CoV-2. We confirmed that 4F not only has antiviral activity against SARS-CoV-2 but also has anti-inflammatory effects in epithelial cells that may alleviate lung injury in COVID-19. Importantly, prior studies have shown that 4F and statins may have major additive in vivo effects on altered lipids, oxidative stress and inflammation that are instigators of cardiovascular disease. Human studies suggest that statin use was associated with a lower risk of developing severe COVID-19. Both statins and 4F attenuate activation of the Toll like Receptor (TLR)-CD147-NF-κB pathways, which are key inflammatory pathways in coronavirus infections. We hypothesize that the combination of 4F and statins has antiviral activity against SARS-CoV-2 in lung epithelial cells and anti-inflammatory activity in lung epithelial cells, macrophages and vascular endothelial cells by attenuating the redox sensitive TLR-CD147-NF-κB proviral and proinflammatory pathway. Thus, in Aim 1 of this proposal and using an air-liquid interface (ALI) culture of primary airway epithelial cells, and cell lines in combination with viral and immune assays, we will determine the mechanisms how the combination of 4F with atorvastatin attenuates aberrant activation of the TLR-CD147-NF-κB pathway as a novel mechanism that drives viral replication and associated inflammatory responses in SARS-CoV-2 infected lung cells. Given that vascular dysfunction is a possible mechanism of chronic post-infectious sequalae of COVID-19, in Aim 2 of this proposal and using an established ex vivo model of atherogenesis and vascular dysfunction and peripheral blood mononuclear cells (PBMCs) from COVID-19 patients in combination with immune assays, we will determine whether 4F and atorvastatin attenuate aberrant activation of the TLR-CD147-NF-κB pathway in macrophages from COVID-19 patients that interact ex vivo with endothelial cells to drive proinflammatory proatherogenic responses. Our independent aims will complement each other and will advance the use of the combination of apoA-I mimetic peptides and statins as novel therapy for COVID-19. This work is innovative, interdisciplinary, public health-oriented, and directly addresses the goals of funding opportunity.

项目总结/摘要 SARS-CoV-2大流行强调迫切需要确定新的靶向途径， 抗病毒药该提案描述了apoA-I模拟物与他汀类药物组合作为新疗法的用途 为COVID-19。SARS-CoV-2利用线粒体在肺上皮细胞中复制。线粒体活性 氧物种（mito-ROS）诱导脂质、膜和氧化还原敏感蛋白的改变， 病毒复制因此，我们假设抗氧化剂ApoA-I模拟肽4F，靶向脂质， mito-ROS和氧化还原途径，具有抗SARS-CoV-2的抗病毒活性。我们确认4F不仅有 抗SARS-CoV-2的抗病毒活性，而且在上皮细胞中具有抗炎作用， COVID-19的肺损伤。重要的是，之前的研究表明，4F和他汀类药物可能在治疗中具有重要作用。 对脂质改变、氧化应激和炎症的体内影响，这些都是心血管疾病的诱因。 人体研究表明，他汀类药物的使用与较低的严重COVID-19风险有关。两 他汀类药物和4F减弱Toll样受体（TLR）-CD 147-NF-κB通路的激活，这是关键 冠状病毒感染的炎症途径。我们假设4F和他汀类药物的联合治疗 肺上皮细胞抗SARS-CoV-2的抗病毒活性和肺上皮细胞的抗炎活性 细胞、巨噬细胞和血管内皮细胞通过减弱氧化还原敏感的TLR-CD 147-NF-κB 前病毒和促炎途径。因此，在该提议的目标1中，使用空气-液体界面（ALI） 原代气道上皮细胞和细胞系的培养与病毒和免疫测定相结合，我们将 确定4F与阿托伐他汀的组合如何减弱异常激活的机制。 TLR-CD 147-NF-κB通路作为驱动病毒复制和相关炎症的新机制 SARS-CoV-2感染的肺细胞的反应。考虑到血管功能障碍可能是 COVID-19的慢性感染后后遗症，在本提案的目标2中，并使用已建立的离体 动脉粥样硬化形成和血管功能障碍的模型和外周血单核细胞（PBMC） COVID-19患者结合免疫测定，我们将确定4F和阿托伐他汀是否 减弱COVID-19患者巨噬细胞中TLR-CD 147-NF-κB通路的异常激活， 与内皮细胞离体相互作用以驱动促炎性促动脉粥样硬化反应。我们的独立 目的将相互补充，并将促进apoA-I模拟肽和 他汀类药物作为新型治疗COVID-19。这项工作是创新的，跨学科的，面向公共卫生， 直接解决了融资机会的目标。