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：
10645137
负责人：
Feng Guo
金额：
$ 47.87万
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/10645137
关键词：
2019-nCoV 3-Dimensional Academia Address Affect Affinity Algorithms Animal Model Antisense Oligonucleotides Antiviral Agents Base Pairing Binding Biochemical Biological 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 Persons Pharmaceutical Preparations Phylogenetic Analysis Predisposition 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 technology platform 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.

项目摘要（摘要）开发针对COVID-19的三维反义寡核苷酸药物 2019年冠状病毒疾病罪魁祸首（COVID-19）大流行，严重的急性呼吸系统综合症有关冠状病毒2（SARS-COV-2）具有非常大的RNA基因组，该基因组编码蛋白质和RNA元素病毒感染和复制的所有方面都需要。该特性使该病毒容易受到新课程的影响称为反义寡核苷酸（ASO）的药物。 ASO是单链的合成核酸，可实现通过Watson-Crick碱基配对与病毒或其他目标RNA结合，治疗效果，这定义了分子生物学和生命的基础。美国食品和药物批准的第一种ASO药物给药是针对巨细胞病毒的抗病毒。开发ASO抗病毒药物的主要挑战是 RNA折叠成干扰ASO杂交的结构的强趋势。当前的ASO设计方法不能充分解决此问题。我们已经开发了一个基于结构的ASO设计技术平台，该平台利用了三个靶RNA的尺寸结构。我们的“ 3D-asos”不仅认识到序列，而且认识 SARS-COV-2 RNA。与传统设计相比，3D-ASOS接触病毒RNA更广泛，并且因此，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使用创新的RNA结构测定方法的3D-ASO药物开发工作流。在初步研究，我们针对SARS-COV-2病毒RNA设计并测试了几个3D-ASO，并确定了两个铅序列强烈抑制培养的人类细胞中病毒复制的程度要大得多先前报道的序列。在拟议的研究中，我们将通过更改其铅3D-ASO来优化铅3D-ASO 主链修饰和基础，以更紧密结合，并更好地适合病毒RNA和更强的抑制作用发挥其功能。我们还将通过设计和测试其他抗SARS-COV-2 3D-ASO来投射网宽。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 候选临床试验的药物。这些药物可以作为鼻喷雾剂或通过静脉注射给予治疗或预防。我们将完善的基于结构的设计技术通常适用于ASO 药物开发。因此，这项研究有可能在战场上与Covid-19和在我们与许多其他疾病的战斗中。