SARS-CoV-2 polymerase inhibitor screening

2019冠状病毒病（COVID-19）是由严重急性呼吸综合征冠状病毒2 （SARS-CoV-2）引起的新出现的全球大流行疾病。COVID-19正在对公共卫生构成巨大威胁，目前没有针对SARS-CoV-2的疫苗和治疗剂。这种新型单链包膜RNA病毒是已知的第七种人类冠状病毒。SARS-CoV-2不同于已知引起普通感冒的其他冠状病毒（229E、OC43、NL63和HKU1），但与2002年的人畜共患严重急性呼吸综合征冠状病毒和2012年的中东呼吸综合征冠状病毒相似。肺炎和呼吸衰竭是这些冠状病毒感染者报告的临床并发症。虽然针对SARS-CoV-2的疫苗和单克隆抗体正在开发中，但目前正在考虑和测试一些研究性疗法，包括临床批准的靶向SARS-CoV-2细胞进入和复制的重新用途药物。例如，病毒聚合酶一直是主要的治疗靶点，正如针对各种病毒病原体（例如，hiv - 1、HCV和HBV）的多种药物发现成功所见。事实上，我们在埃默里大学药物发现中心（CDD）的化学团队（由Dr. R. F. Schinazi领导）之前已经发现了几种核苷/核苷酸病毒聚合酶抑制剂，包括拉米夫定（3TC）和恩曲他滨（FTC），用于治疗HIV，以及索非布韦用于治疗HCV。基于这一成功的机制策略，我们目前针对SARS-CoV-2的策略方法是用可能抑制病毒复制的特定核苷化合物靶向其病毒RNA依赖性RNA聚合酶。在这个竞争性修订应用程序中，我们选择了一个高选择性和化学多样性的核苷/核苷酸RNA聚合酶抑制剂文库，其中包括200种化合物。我们之前已经使用我们的体外毒性筛选试验建立了这组化合物的安全毒性概况，该试验由一组关键细胞系组成，包括人类原代细胞。我们的目标是利用我们建立的体外SARS-CoV-2病毒培养和病毒测定系统来研究每种化合物的抗病毒功效。

Coronavirus disease 2019 (COVID-19) is an emerging global pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). COVID-19 is imposing a tremendous public health threat, with no vaccines and therapeutic agents against SARS-CoV-2 currently available. This novel single-stranded enveloped RNA virus is the seventh known human coronavirus. SARS-CoV-2 is unlike the other coronaviruses known to cause the common cold (229E, OC43, NL63, and HKU1), but similar to the zoonotic severe acute respiratory syndrome coronavirus from 2002 and the Middle East respiratory syndrome coronavirus from 2012. Pneumonia and respiratory failure are the reported clinical complications of the infected by these coronaviruses. While vaccines and monoclonal antibodies against SARS-CoV-2 are in development, a number of investigational therapies are currently being considered and tested, including repurposed clinically approved drugs targeting SARS-CoV-2 cell entry and replication. For example, viral polymerases have been major therapeutic targets, as seen in multiple drug discovery successes targeting various viral pathogens (e.g., HIV1, HCV, and HBV). In fact, the chemistry team of our Center for Drug Discovery (CDD) at Emory University (led by Dr. R. F. Schinazi), have previously discovered several nucleoside/nucleotide viral polymerase inhibitors including lamivudine (3TC) and emtricitabine (FTC) to treat HIV, as well as sofosbuvir to cure HCV. Building on this successful mechanistic strategy, our current strategic approach for SARS-CoV-2 is to target its viral RNA-dependent RNA polymerase with specific nucleoside compounds that could potentially inhibit viral replication. In this competitive revision application, we have chosen a highly selective and chemically diverse nucleoside/nucleotide RNA polymerase inhibitor library, which consists of 200 compounds. We have previously established a safe toxicity profile for this set of compounds using our in vitro toxicity screening assay that consists of a panel of key cell-lines including human primary cells. Our goal is to investigate the antiviral efficacy of each of these compounds by employing our established in vitro SARS-CoV-2 virus culture and viral assay system.