Develop broad-spectrum antiviral agents against COVID-19 based on innate immune response to SARS-CoV-2 infection

基于对 SARS-CoV-2 感染的先天免疫反应，开发针对 COVID-19 的广谱抗病毒药物

• 批准号: 10222540
• 负责人: GENHONG CHENG
• 金额: $ 38.03万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10222540
• 关键词: 2019-nCoV; Antiviral Agents; Avian Influenza; Blinded; COVID-19; COVID-19 pandemic; COVID-19 patient; COVID-19 treatment; Cell membrane; Cells; Cholesterol; Complex; Consumption; Coronavirus; Coronavirus Infections; Deubiquitinating Enzyme; Disease; Disease Outbreaks; Down-Regulation; Drug Targeting; Ebola; Emerging Communicable Diseases; Enzymes; Fatty-acid synthase; Genes; Goals; HIV; Human; Immune system; Infection; Influenza; Innate Immune Response; Interferon Type I; Interferons; Knock-out; Laboratories; Learning; Malignant Neoplasms; Mediating; Metabolic; Mixed Function Oxygenases; Murine hepatitis virus; Neuraminidase; Papain; Paper; Pathway interactions; Peptide Hydrolases; Pharmaceutical Preparations; Play; Publishing; RNA Virus Infections; RNA-Directed DNA Polymerase; Reapplication; Role; SARS-CoV-2 infection; SARS-CoV-2 inhibitor; Serum; Severe Acute Respiratory Syndrome; Signal Pathway; Signal Transduction Pathway; TNF receptor-associated factor 3; Therapeutic Agents; Time; Toxic effect; Ubiquitination; Up-Regulation; Viral; Virus; Virus Diseases; Virus Replication; ZIKA; Zika Virus; analog; base; combat; drug development; fight against; inhibitor/antagonist; knock-down; long chain fatty acid; novel; novel strategies; overexpression; pathogenic virus; prevent; programs; response; small molecule; therapeutically effective

ABSTRACT The goals of this proposal are to determine the type I interferon (IFN-I)-mediated antiviral gene program against SARS-CoV-2 infection and to develop novel broad-spectrum antiviral agents (BSAAs) for the treatment of COVID-19 and other emerging infectious diseases. There are no effective therapeutic agents currently available in the fight against the global COVID-19 pandemic, in which SARS-CoV-2 has infected millions of people in confirmed cases and caused hundreds of thousands of fatalities. Drugs that target a single virus, like the inhibitors of HIV reverse transcriptase and influenza neuraminidase, require a comprehensive understanding of the lifecycle and disease mechanisms of the virus, which makes development of these drugs necessarily time-consuming. Outbreaks of infection caused by novel emerging highly pathogenic viruses, including avian influenza, SARS, Ebola, Zika virus (ZIKV) and SARS-CoV-2, have become a major concern in the past two decades. We cannot rely on the traditional virus-specific drugs to treat diseases caused by these unpredictable emerging viruses. Therefore, it is extremely important to develop BSAAs effective against a range of viruses. My laboratory has been studying anti-viral innate immune responses, particularly the IFN-I signaling pathway and its downstream gene program, for the last 20 years. While the field has previously focused only on interferon-stimulated genes (ISGs), we have demonstrated that ISGs like cholesterol 25- hydroxylase (CH25H) and IFN-I downregulated genes like fatty acid synthase (FASN) both play important roles in limiting viral infection and replication. We have also identified multiple small molecules for use as BSAAs, including 25-hydroxycholersterol (25HC), the metabolic product of CH25H, and the FASN inhibitor C75. In addition, we have extensively studied host innate immune responses to coronaviral infection: we have published multiple papers that explain how the host IFN-I signal transduction pathway is activated in response to infection by coronaviruses like murine hepatitis virus (MHV) and how coronaviruses can suppress their host’s innate immune responses through the viral papain-like protease (PLpro). Most importantly, in our preliminary studies we found that 25HC and C75 both have strong inhibitory effects against SARS-CoV-2 infection. We hypothesize that the IFN-I-mediated antiviral gene program involves not only upregulation of antiviral ISGs but also downregulation of the host genes required for viral infection and replication. We further hypothesize that by identifying the IFN-I-mediated antiviral gene program against SARS-CoV-2, we will be able to develop novel antiviral agents to combat COVID-19 and other emerging threats. In this proposal, we will first determine the IFN-I gene program in innate immune response to SARS-CoV-2. We will also develop 25HC, 25HC analogs and FASN inhibitors as novel antiviral agents against SARS-CoV-2. We believe our studies will not only determine the IFN-I-mediated antiviral gene program in host innate immune response to SARS-CoV-2 infection but also develop BSAAs to treat COVID-19 and other emerging infectious diseases.

摘要 本提案的目的是确定I型干扰素（IFN-I）介导的抗病毒基因程序 针对SARS-CoV-2感染，并开发新的广谱抗病毒药物（BSAA）用于治疗 COVID-19和其他新出现的传染病。目前尚无有效的治疗药物 在抗击全球COVID-19大流行的斗争中，SARS-CoV-2已感染了数百万人， 确诊病例已造成数十万人死亡。针对单一病毒的药物，如 艾滋病毒逆转录酶和流感神经氨酸酶的抑制剂，需要一个全面的 了解病毒的生命周期和疾病机制，这使得这些药物的开发 必然是耗时的。新出现的高致病性病毒引起的感染爆发， 包括禽流感、SARS、埃博拉、寨卡病毒（ZIKV）和SARS-CoV-2，已成为 过去的二十年我们不能依靠传统的病毒特异性药物来治疗这些疾病 不可预测的新兴病毒因此，开发有效的BSAA对 一系列病毒。我的实验室一直在研究抗病毒的先天免疫反应，特别是干扰素-I 信号通路及其下游基因程序，在过去的20年里。虽然该领域以前 仅关注干扰素刺激基因（ISGs），我们已经证明ISGs像胆固醇25- 羟化酶（CH 25 H）和IFN-I下调的基因如脂肪酸合成酶（FATCH）都起重要作用 限制病毒感染和复制。我们还鉴定了多种用作BSAA的小分子， 包括25-羟基胆固醇（25 HC），CH 25 H的代谢产物，以及FcB抑制剂C75。在 此外，我们还广泛研究了宿主对冠状病毒感染的先天免疫反应： 发表了多篇论文，解释了宿主IFN-I信号转导通路如何在应答中被激活 感染冠状病毒，如鼠肝炎病毒（MHV），以及冠状病毒如何抑制其 通过病毒木瓜蛋白酶样蛋白酶（PLpro）的宿主的先天免疫反应。最重要的是，在我们 初步研究发现，25 HC和C75对SARS-CoV-2均有较强的抑制作用 感染我们推测，干扰素-I介导的抗病毒基因程序不仅涉及上调 抗病毒ISG，但也下调病毒感染和复制所需的宿主基因。我们进一步 假设通过鉴定IFN-1介导的抗SARS-CoV-2的抗病毒基因程序，我们将能够 开发新型抗病毒药物，以对抗COVID-19和其他新兴威胁。在这份提案中，我们将首先 确定IFN-I基因在SARS-CoV-2天然免疫应答中的作用。我们还将开发25 HC， 25 HC类似物和Festival抑制剂作为抗SARS-CoV-2的新型抗病毒剂。我们相信我们的研究 不仅确定了IFN-Ⅰ介导的抗病毒基因程序在宿主对SARS-CoV-2的先天免疫应答中的作用， 感染，而且还开发BSAA来治疗COVID-19和其他新出现的传染病。