Developing three-dimensional antisense oligonucleotide drugs against COVID-19

开发针对COVID-19的三维反义寡核苷酸药物

• 批准号: 10280762
• 负责人: Feng Guo
• 金额: $ 42.66万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-19 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10280762
• 关键词: 2019-nCoV; 3-Dimensional; Academia; Address; Affect; Affinity; Algorithms; Animal Model; Antisense Oligonucleotides; Antiviral Agents; Base Pairing; Binding; Biochemical; Biological Response Modifier Therapy; COVID-19; COVID-19 pandemic; COVID-19 treatment; Cells; Cessation of life; Chemicals; Clinical Trials; Communicable Diseases; Complex; Cytomegalovirus; Data; Development; Disease; Elements; Emergency Situation; Emerging Communicable Diseases; Feedback; Formulation; Foundations; Free Energy; Genetic Transcription; Genome; Goals; Human; Hydrogen Bonding; Industry; Lead; Life; Literature; Methods; Modification; Molecular Biology; Monitor; Mus; Mutation; Nose; Nucleic Acids; Oligonucleotides; Pathogenicity; Pattern; Pharmaceutical Preparations; Phylogenetic Analysis; Prevention; Production; Program Development; Property; Proteins; RNA; RNA Viruses; Reporting; Research; SARS-CoV-2 inhibitor; Shapes; Site; Specificity; Structure; Symptoms; Technology; Testing; Therapeutic Effect; United States Food and Drug Administration; Vaccines; Vertebral column; Viral; Virus; Virus Diseases; Virus Replication; base; design; drug candidate; drug development; drug resistant virus; fighting; health care availability; high risk; improved; in vivo; innovation; innovative technologies; intravenous injection; lead optimization; mouse model; novel drug class; novel therapeutics; pandemic disease; prevent; remdesivir; synthetic nucleic acid; three dimensional structure; viral RNA

Project Summary (Abstract) Developing three-dimensional antisense oligonucleotide drugs against COVID-19 The culprit of coronavirus disease 2019 (COVID-19) pandemic, severe acute respiratory syndrome-related coronavirus-2 (SARS-CoV-2), has a very large RNA genome that encodes the proteins and RNA elements required for all aspects of viral infection and replication. This property makes the virus vulnerable to a new class of drugs called antisense oligonucleotide (ASO). ASOs are single-stranded synthetic nucleic acids that achieve therapeutic effects by binding to viral or other target RNAs via Watson-Crick base pairing, the very interaction that defines molecular biology and the foundation of life. The first ASO drug approved by the U.S. Food and Drug Administration is an antiviral against cytomegalovirus. A major challenge of developing ASO antiviral drugs is the strong tendency of RNA to fold into structures that interfere with ASO hybridization. Current ASO design methods do not adequately address this problem. We have developed a structure-based ASO design technology platform that takes advantage of three- dimensional structures of target RNAs. Our “3D-ASOs” recognize not only the sequences but also the shapes of SARS-CoV-2 RNAs. Compared to conventional designs, 3D-ASOs contact viral RNAs more extensively and therefore can achieve greater affinity and specificity. Our technology platform includes four design templates and a 3D-ASO drug development workflow that employs an innovative RNA structure determination method. In a preliminary study, we designed and tested several 3D-ASOs against SARS-CoV-2 viral RNA and identified two lead sequences that strongly inhibit viral replication in cultured human cells to a much greater extent than previously reported sequences. In the proposed research, we will optimize the lead 3D-ASOs by altering their backbone modifications and bases for tighter binding and better fit to the viral RNAs and for stronger inhibition to their functions. We will also cast our net wide by designing and testing additional anti-SARS-CoV-2 3D-ASOs. Finally, the most potent 3D-ASOs will be tested in an animal model. If successful, the project will provide ASO drug candidates for clinical trials. These drugs may be given as nasal sprays or via intravenous injection, as treatments or for prevention. The structure-based design technology we will refine is generally applicable to ASO drug development. Therefore, this research has the potential to turn tide on the battlefield against COVID-19 and in our fight with many other diseases.

项目摘要（摘要） 开发抗COVID-19的三维反义寡核苷酸药物 2019冠状病毒病（COVID-19）大流行的罪魁祸首，严重急性呼吸综合征相关 冠状病毒2型（SARS-CoV-2）具有非常大的RNA基因组，其编码蛋白质和RNA元件 病毒感染和复制的各个方面都需要。这种特性使病毒容易受到一个新类的攻击 反义寡核苷酸（阿索）。ASO是单链合成核酸， 通过沃森-克里克碱基配对与病毒或其他靶RNA结合， 定义了分子生物学和生命的基础。美国食品和药物管理局批准的第一个阿索药物 给药是一种抗巨细胞病毒的抗病毒药物。开发阿索抗病毒药物的主要挑战是 RNA折叠成干扰阿索杂交的结构的强烈趋势。当前阿索设计 这些方法不能充分解决这个问题。 我们开发了一个基于结构的阿索设计技术平台，该平台利用了三个方面的优势- 靶RNA的三维结构。我们的“3D-ASO”不仅可以识别序列，还可以识别 SARS-CoV-2 RNA。与常规设计相比，3D-ASO更广泛地接触病毒RNA， 因此可以获得更大的亲和力和特异性。我们的技术平台包括四个设计模板， 3D-ASO药物开发工作流程，采用创新的RNA结构测定方法。中 初步研究，我们设计并测试了几种针对SARS-CoV-2病毒RNA的3D-ASO，并鉴定了两种 在培养的人细胞中强烈抑制病毒复制的前导序列比 先前报道的序列。在拟议的研究中，我们将通过改变其 骨架修饰和碱基，用于更紧密的结合，更好地适合病毒RNA，并具有更强的抑制作用 他们的职能。我们亦会广撒网，设计及测试更多抗SARS-CoV-2的3D-ASO。 最后，最有效的3D-ASO将在动物模型中进行测试。如果成功，该项目将提供阿索 用于临床试验的候选药物。这些药物可以作为鼻喷雾剂或通过静脉注射给药， 治疗或预防。我们将细化的基于结构的设计技术普遍适用于阿索 药物开发因此，这项研究有可能在对抗COVID-19的战场上扭转局势， in our fight战斗with many许多other diseases疾病.