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征（SARS）-冠状病毒（CoV）-2引起的COVID-19大流行需要生物医学研究人员迅速采取行动，研究病毒生命周期的关键步骤，并确定病毒复制靶点，以进行分子干预，从而获得治疗方案。该项目的重点是SARS-CoV-2（Nsp 13）解旋酶的分子特征，对冠状病毒复制至关重要。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 Nsp 12 RNA依赖性RNA聚合酶1的伙伴关系的基本理解。高通量筛选，以确定小分子干扰的催化功能和相互作用的SARS-CoV-2解旋酶将提供一个战略，削弱病毒复制，一个范例，建立在正在进行的研究Nsp 12聚合酶靶向化合物Remdesivir 2。候选COVID-19解旋酶抑制剂的发现可能会导致一种新的治疗性抗病毒方法，可用作单一疗法或与正在使用或开发的抗病毒药物的联合疗法。 COVID-19对老龄化人口构成特殊挑战，他们往往有潜在的医疗条件3。与糖尿病相关的合并症、免疫衰老、养老院感染和疾病的风险较高以及老年人社交距离的并发症可能导致老年人死亡风险升高。免疫功能障碍和受损的病毒（免疫）发病机制是影响未来老年人COVID-19疫苗功效的重要因素。因此，抗病毒治疗，最终与免疫策略相结合，将是有利的。这项COVID-19研究计划的重点是SARS-CoV-2复制的一个关键靶点（解旋酶），并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.