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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要（摘要）开发针对COVID-19的三维反义寡核苷酸药物 2019年冠状病毒病（COVID-19）大流行的罪魁祸首，与严重急性呼吸道综合症有关冠状病毒-2 (SARS-CoV-2) 具有非常大的 RNA 基因组，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，使得该病毒容易受到新类别的影响。称为反义寡核苷酸药物（ASO）是单链合成核酸，可实现。通过 Watson-Crick 碱基配对（这种相互作用）与病毒或其他靶标 RNA 结合，从而产生治疗效果定义了分子生物学和生命的基础，是美国食品药品监督管理局批准的第一个 ASO 药物。给药是针对巨细胞病毒的抗病毒药物，开发 ASO 抗病毒药物的一个主要挑战是。 RNA 强烈倾向于折叠成干扰 ASO 杂交的结构。方法并不能充分解决这个问题。我们开发了一个基于结构的 ASO 设计技术平台，该平台利用了三个优势：我们的“3D-ASO”不仅可以识别序列，还可以识别目标 RNA 的形状。与传统设计相比，3D-ASO 更广泛地接触病毒 RNA。因此可以实现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和 3D-ASO 药物开发工作流程采用创新的 RNA 结构测定方法。在初步研究中，我们设计并测试了几种针对 SARS-CoV-2 病毒 RNA 的 3D-ASO，并确定了两种在培养的人类细胞中强烈抑制病毒复制的先导序列，其程度比在之前报道的研究中，我们将通过改变领先的 3D-ASO 来优化它们。主链修饰和碱基可实现更紧密的结合、更好地贴合病毒 RNA 以及更强的抑制作用我们还将通过设计和测试其他抗 SARS-CoV-2 3D-ASO 来广泛撒网。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 ASO。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。我们将完善的基于结构的设计技术普遍适用于ASO。因此，这项研究有可能扭转抗击 COVID-19 的战场局势。在我们与许多其他疾病的斗争中。