SARS-CoV-2 polymerase inhibitor screening

2019年冠状病毒病(新冠肺炎)是由严重急性呼吸综合征冠状病毒2型(SARS-CoV-2)引起的一种新兴的全球大流行。新冠肺炎正在对公众健康构成巨大威胁，目前还没有针对SARS-CoV-2的疫苗和治疗剂可用。这种新的单链包膜RNA病毒是已知的第七种人类冠状病毒。SARS-CoV-2与已知的导致普通感冒的其他冠状病毒(229E、OC43、NL63和HKU1)不同，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。据报道，肺炎和呼吸衰竭是这些冠状病毒感染者的临床并发症。虽然针对SARS-CoV-2的疫苗和单抗正在开发中，但目前正在考虑和测试一些研究疗法，包括针对SARS-CoV-2细胞进入和复制的改变用途的临床批准药物。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(如HIV1、丙型肝炎病毒和乙肝病毒)的多项药物发现成功所看到的那样。事实上，我们埃默里大学药物发现中心(CDD)的化学团队(由R.F.Schinazi博士领导)之前已经发现了几种核苷/核苷酸病毒聚合酶抑制剂，包括治疗HIV的拉米夫定(3TC)和恩曲他滨(FTC)，以及治疗丙型肝炎的索莫布韦。在这一成功的机械策略的基础上，我们目前针对SARS-CoV-2的战略方法是以其病毒RNA依赖的RNA聚合酶为靶点，使用特定的核苷化合物，这些化合物可能会潜在地抑制病毒复制。在这一竞争性修订应用中，我们选择了一个高度选择性和化学多样性的核苷/核苷酸RNA聚合酶抑制物库，它由200个化合物组成。我们之前已经使用我们的体外毒性筛选试验为这一组化合物建立了安全的毒性曲线，该试验由包括人类原代细胞在内的一组关键细胞系组成。我们的目标是利用我们建立的SARS-CoV-2病毒体外培养和病毒检测系统来研究这些化合物的抗病毒效果。

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.