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: 10669717
• 负责人: MICHAEL E JUNG
• 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/10669717
• 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; Life Cycle Stages; Malignant Neoplasms; Mediating; Metabolic; Mixed Function Oxygenases; Murine hepatitis virus; Neuraminidase; Papain; Paper; Pathway interactions; Peptide Hydrolases; Persons; Pharmaceutical Preparations; Play; Publishing; RNA Virus Infections; RNA-Directed DNA Polymerase; Reapplication; Role; SARS-CoV-2 infection; SARS-CoV-2 inhibitor; SARS-CoV-2 protease; Serum; Severe Acute Respiratory Syndrome; Signal Pathway; Signal Transduction Pathway; TNF receptor-associated factor 3; Therapeutic Agents; Time; Toxic effect; Ubiquitination; Up-Regulation; Viral; Viral Genes; Viral Physiology; Virus; Virus Diseases; Virus Replication; ZIKA; Zika Virus; analog; combat; drug development; fighting; inhibitor; knock-down; long chain fatty acid; novel; novel strategies; overexpression; pathogenic virus; prevent; programs; response; small molecule; therapeutically effective; ubiquitin isopeptidase

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 该建议的目标是确定I型干扰素（IFN-I）介导的抗病毒药基因程序 反对SARS-COV-2感染并开发新的广谱抗病毒剂（BSAA）进行治疗 Covid-19和其他新兴的传染病。目前没有有效的治疗剂 在与全球Covid-19大流行的战斗中可用于SARS-COV-2感染数百万 确认案件的人并造成了数十万死亡。靶向单个病毒的药物 艾滋病毒逆转录酶和影响力的抑制剂需要全面 了解病毒的生命周期和疾病机制，这使这些药物开发 一定是耗时的。由新兴的高致病病毒引起的感染爆发， 包括鸟类影响 过去二十年。我们不能依靠传统病毒特异性药物来治疗由这些药物引起的疾病 不可预测的新兴病毒。因此，开发有效的BSAA非常重要 病毒范围。我的实验室一直在研究抗病毒先天免疫反应，尤其是IFN-I 在过去的20年中，信号通路及其下游基因程序。虽然该领域以前有 仅专注于干扰素刺激的基因（ISGS），我们已经证明了ISGS胆固醇等25-- 羟化酶（CH25H）和IFN-I下调基因（如脂肪酸合酶（FASN））都起着重要作用 在限制病毒感染和复制中。我们还确定了多个小分子作为BSAA， 包括25-羟基胆固醇（25HC），CH25H的代谢产物和FASN抑制剂C75。在 此外，我们对冠状病毒感染进行了广泛研究的宿主先天免疫回报：我们有 发表了多篇论文，解释了主机IFN-I信号传输途径如何激活 诸如鼠类肝炎病毒（MHV）等冠状病毒感染以及冠状病毒如何抑制其 宿主通过病毒木瓜蛋白酶样蛋白酶（PLPRO）的先天免疫反应。最重要的是，在我们的 初步研究我们发现，25HC和C75对SARS-COV-2都有很强的抑制作用 感染。我们假设IFN-I介导的抗病毒基因程序不仅涉及上调 抗病毒ISG，但也下调了病毒感染和复制所需的宿主基因。我们进一步 假设通过确定针对SARS-COV-2的IFN-I介导的抗病毒基因程序，我们将能够 开发新型的抗病毒剂来对抗Covid-19和其他新兴威胁。在此提案中，我们将首先 确定对SARS-COV-2的先天免疫反应中的IFN-I基因程序。我们还将开发25hc， 25HC类似物和FASN抑制剂是针对SARS-COV-2的新型抗病毒剂。我们相信我们的学习将会 不仅确定宿主对SARS-COV-2的先天免疫反应中的IFN-I介导的抗病毒基因程序 感染但也会发展为治疗Covid-19和其他新兴感染的BSAA。

项目成果

The Evolutionary Dance between Innate Host Antiviral Pathways and SARS-CoV-2.

• DOI: 10.3390/pathogens11050538
• 发表时间: 2022-05-03
• 期刊: Pathogens (Basel, Switzerland)

Suppressing fatty acid synthase by type I interferon and chemical inhibitors as a broad spectrum anti-viral strategy against SARS-CoV-2.

• DOI: 10.1016/j.apsb.2022.02.019
• 发表时间: 2022-04
• 期刊: Acta pharmaceutica Sinica. B
• 作者: Aliyari SR;Ghaffari AA;Pernet O;Parvatiyar K;Wang Y;Gerami H;Tong AJ;Vergnes L;Takallou A;Zhang A;Wei X;Chilin LD;Wu Y;Semenkovich CF;Reue K;Smale ST;Lee B;Cheng G
• 通讯作者: Cheng G

Identification of an immunogenic epitope and protective antibody against the furin cleavage site of SARS-CoV-2.

• DOI: 10.1016/j.ebiom.2022.104401
• 发表时间: 2023-01
• 期刊: EBIOMEDICINE
• 影响因子: 11.1
• 作者: Li, Lili;Gao, Meiling;Li, Jie;Xie, Xuping;Zhao, Hui;Wang, Yanan;Xu, Xin;Zu, Shulong;Chen, Chunfeng;Wan, Dingyi;Duan, Jing;Wang, Jingfeng;Aliyari, Saba R.;Gold, Sarah;Zhang, Jicai;Qin, Cheng-Feng;Shi, Pei-Yong;Yang, Heng;Cheng, Genhong
• 通讯作者: Cheng, Genhong

SARS-CoV-2 virus NSP14 Impairs NRF2/HMOX1 activation by targeting Sirtuin 1.

• DOI: 10.1038/s41423-022-00887-w
• 发表时间: 2022-08
• 期刊: CELLULAR & MOLECULAR IMMUNOLOGY
• 影响因子: 24.1
• 作者: Zhang, Shilei;Wang, Jingfeng;Wang, Lulan;Aliyari, Saba;Cheng, Genhong
• 通讯作者: Cheng, Genhong

Protease cleavage of RNF20 facilitates coronavirus replication via stabilization of SREBP1.

• DOI: 10.1073/pnas.2107108118
• 发表时间: 2021-09-14
• 期刊: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1
• 作者: Zhang S;Wang J;Cheng G
• 通讯作者: Cheng G