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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）