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

由新型严重急性呼吸系统综合症-冠状病毒2型引起的新冠肺炎大流行要求生物医学研究人员迅速采取行动，研究病毒生命周期中的关键步骤，并确定病毒复制靶点，以进行分子干预，从而找到治疗方案。本项目主要研究冠状病毒复制所必需的SARS-CoV-2(Nsp13)解旋酶的分子特征。对SARS-CoV-2解旋酶的分析将促进我们对其作用机制以及与SARS-CoV-2 Nsp12依赖RNA的RNA聚合酶1的基本理解。高通量筛选以确定干扰SARS-CoV-2解旋酶催化功能和相互作用的小分子将提供一种削弱病毒复制的策略，这一范式建立在正在进行的针对化合物Remdesivir2的Nsp12聚合酶研究的基础上。候选新冠肺炎解旋酶抑制剂的发现可能导致一种新的治疗方法，适用于单一疗法或与正在使用或开发的抗病毒药物联合治疗。 新冠肺炎对老龄化人口构成了特殊的挑战，他们往往有潜在的医疗条件3。与年龄相关的并存状况、免疫衰老、养老院感染和疾病的较高风险以及老年人社会疏远的并发症可能会增加老年人的死亡风险。免疫功能障碍和受损的病毒(免疫)致病机制是影响未来老年新冠肺炎疫苗疗效的重要因素。因此，最终与免疫策略相结合的抗病毒疗法将是有利的。这项新冠肺炎的研究计划集中在一个关键的SARS-CoV-2复制靶点(解旋酶)和发现小分子抑制剂作为抗病毒药物。

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.