Molecular Characterization of the SARS-CoV-2 Helicase and High-Throughput Screening to Identify Small Molecule SARS-CoV-2 Helicase Inhibitors as Anti-Viral Medicines

SARS-CoV-2 解旋酶的分子表征和高通量筛选以鉴定小分子 SARS-CoV-2 解旋酶抑制剂作为抗病毒药物

• 批准号: 10913114
• 负责人: Robert Brosh
• 金额: $ 28.5万
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10913114
• 关键词: 2019-nCoV; Antiviral Agents; Antiviral Therapy; Binding; Biochemical; Biological Assay; COVID-19; COVID-19 pandemic; Collection; Combined Modality Therapy; Coronavirus; Development; Elderly; Future; Goals; Immune; Immune System Diseases; Immunologics; Individual; Intervention; Life Cycle Stages; Medical; Medicine; Molecular; Molecular Bank; Molecular Target; Nucleic Acids; Nucleotides; Nursing Homes; Pathogenesis; Polymerase; Proteins; RNA; RNA-Directed RNA Polymerase; Research Personnel; Research Proposals; Resolution; SARS-CoV-2 inhibitor; Social Distance; Structure; Structure-Activity Relationship; Therapeutic; Vaccines; Viral; Virus; Virus Replication; age related; aged; aging population; biophysical properties; comorbidity; helicase; high risk; high throughput screening; immunosenescence; infection risk; inhibitor; mortality risk; novel; novel therapeutics; remdesivir; repository; small molecule; small molecule inhibitor; small molecule libraries

The COVID-19 Pandemic caused by the novel Severe Acute Respiratory Syndrome (SARS)- Coronavirus (CoV)-2 has necessitated prompt action by biomedical researchers to study key steps in the virus life cycle and identify viral replication targets for molecular interventions leading to therapeutic options. This project focuses on molecular characterization of SARS-CoV-2 (Nsp13) helicase essential for coronavirus replication. Analyses of SARS-CoV-2 helicase will advance our fundamental understanding of its mechanism-of-action and partnership with SARS-CoV-2 Nsp12 RNA-dependent RNA polymerase1. High-throughput screens to identify small molecules that interfere with catalytic functions and interactions of SARS-CoV-2 helicase will provide a strategy for crippling viral replication, a paradigm that builds upon ongoing studies of the Nsp12 polymerase targeting compound Remdesivir2. Discovery of candidate COVID-19 helicase inhibitors may lead to a novel therapeutic anti-viral approach applicable as mono-therapy or combination therapy with anti-viral drugs in use or development. COVID-19 poses a special challenge for the aging population who often have underlying medical conditions3. Age-related comorbid conditions, immuno-senescence, higher risk for infection and sickness in nursing homes, and complications of social distancing for older people likely contribute to elevated risk of mortality for aged individuals. Immune dysfunction and compromised virus (immune) pathogenesis are significant factors influencing the efficacy of future vaccines against COVID-19 for the elderly. Consequently, anti-viral therapies, ultimately combined with immunological strategies, will be advantageous. This COVID-19 research proposal is focused on a key SARS-CoV-2 replication target (helicase) and discovery of small molecule inhibitors as antiviral medicines.

新型严重的急性呼吸综合征（SARS）引起的COVID-19大流行 - 冠状病毒（COV）-2使生物医学研究人员迅速采取了研究病毒生命周期中的关键步骤，并确定病毒复制靶标的分子干预措施，导致治疗方案。该项目的重点是SARS-COV-2（NSP13）的分子表征，对冠状病毒复制必不可少。 SARS-COV-2解旋酶的分析将提高我们对其行动机理和与SARS-COV-2 NSP12 RNA依赖性RNA聚合酶1的基本理解。高通量筛选以识别干扰催化功能和SARS-COV-2解旋酶相互作用的小分子，将为削弱病毒复制的策略提供策略，这是一种基于对NSP12聚合酶靶向靶向化合物remdesivir2的持续研究的范式。发现候选候选菌酶抑制剂的候选者可能导致一种新型的治疗性抗病毒方法，可作为单疗法或使用抗病毒药物的单疗法或联合疗法使用或发育。 Covid-19对经常患有潜在医疗条件的老龄化人群提出了一个特别的挑战3。与年龄相关的合并症，免疫年份，疗养院中感染和疾病的风险更高以及老年人的社会疏远并发症可能导致老年人死亡的风险升高。免疫功能障碍和病毒（免疫）发病机理是影响未来疫苗对COVID-19对老年人的疗效的重要因素。因此，抗病毒疗法最终与免疫学策略相结合，将是有利的。这项COVID-19研究建议集中于关键的SARS-COV-2复制靶标（解旋酶）和将小分子抑制剂作为抗病毒药物的发现。