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

基本信息

批准号：
10174522
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
项目类别：
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/10174522
关键词：
2019-nCoV Antiviral Agents Avian Influenza Blinded COVID-19 COVID-19 pandemic 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 Patients Peptide Hydrolases Pharmaceutical Preparations Play Publishing RNA Virus Infections RNA-Directed DNA Polymerase Reapplication Role Serum Severe Acute Respiratory Syndrome Signal Pathway Signal Transduction Pathway TNF receptor-associated factor 3 Therapeutic Agents Time Toxic effect Treatment Efficacy 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

项目摘要

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.

抽象的该提案的目标是确定 I 型干扰素 (IFN-I) 介导的抗病毒基因程序对抗 SARS-CoV-2 感染并开发新型广谱抗病毒药物 (BSAA) 进行治疗 COVID-19 和其他新发传染病目前尚无有效的治疗药物。可用于抗击全球 COVID-19 大流行，其中 SARS-CoV-2 已感染数百万人针对单一病毒的药物，如确诊病例，导致数十万人死亡。 HIV逆转录酶和流感神经氨酸酶抑制剂，需要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新型高致病性病毒引起的感染爆发必然耗时，包括禽流感、SARS、埃博拉病毒、寨卡病毒 (ZIKV) 和 SARS-CoV-2，已成为人们关注的主要问题在过去的二十年里，我们不能依靠传统的病毒特异性药物来治疗由这些病毒引起的疾病。因此，开发有效对抗新出现的病毒的 BSAA 非常重要。我的实验室一直在研究抗病毒先天免疫反应，特别是 IFN-I。信号通路及其下游基因程序，在过去的 20 年里，而该领域以前。仅关注干扰素刺激基因 (ISG)，我们已经证明 ISG 与胆固醇类似 25- 羟化酶 (CH25H) 和 IFN-I 下调基因，如脂肪酸合酶 (FASN) 都发挥着重要作用我们还发现了多种小分子可用作 BSAA，包括 25-羟基胆固醇 (25HC)、CH25H 的代谢产物和 FASN 抑制剂 C75。此外，我们主要研究了宿主对冠状病毒感染的先天免疫反应：我们有发表多篇论文解释宿主 IFN-I 信号转导通路如何被激活以响应鼠肝炎病毒 (MHV) 等冠状病毒感染以及冠状病毒如何抑制其感染最重要的是，在我们的体内，宿主通过病毒类木瓜蛋白酶（PLpro）进行先天免疫反应。初步研究发现25HC和C75对SARS-CoV-2都有较强的抑制作用我们认为 IFN-I 介导的抗病毒基因程序不仅涉及上调。抗病毒 ISG 还下调病毒感染和复制所需的宿主基因。通过识别 IFN-I 介导的针对 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来对抗 COVID-19 和其他新出现的威胁在本提案中，我们将首先。确定 SARS-CoV-2 先天免疫反应中的 IFN-I 基因程序我们还将开发 25HC， 25HC 类似物和 FASN 抑制剂作为针对 SARS-CoV-2 的新型抗病毒药物。不仅确定了宿主对 SARS-CoV-2 的先天免疫反应中 IFN-I 介导的抗病毒基因程序感染，还开发 BSAA 来治疗 COVID-19 和其他新出现的传染病。