SARS-CoV-2 polymerase inhibitor screening

SARS-CoV-2聚合酶抑制剂筛选

• 批准号: 10230304
• 负责人: Baek Kim
• 金额: $ 20.8万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-18 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10230304
• 关键词: 2019-nCoV; Biological Assay; COVID-19; Cell Line; Cells; Chemicals; Chemistry; Clinical; Common Cold; Coronavirus; Development; Drug Targeting; Goals; HIV; HIV-1; Hepatitis B Virus; Hepatitis C virus; Human; In Vitro; Investigational Therapies; Lamivudine; Libraries; Middle East Respiratory Syndrome Coronavirus; Monoclonal Antibodies; Nucleosides; Nucleotides; Pneumonia; Polymerase; Public Health; RNA Polymerase Inhibitor; RNA Viruses; RNA-Directed RNA Polymerase; Reporting; Respiratory Failure; SARS coronavirus; System; Testing; Therapeutic Agents; Toxic effect; Universities; Vaccines; Viral; Virus Replication; Zoonoses; anti-viral efficacy; drug discovery; emtricitabine; human coronavirus; inhibitor/antagonist; novel; pandemic disease; pathogenic virus; screening; success; therapeutic target; viral RNA; virus culture

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.

2019年冠状病毒病（COVID-19）是由严重急性呼吸道综合征冠状病毒2（SARS-CoV-2）引起的一种新兴全球大流行病。COVID-19正在对公共卫生构成巨大威胁，目前还没有针对SARS-CoV-2的疫苗和治疗药物。这种新型单链包膜RNA病毒是第七种已知的人类冠状病毒。SARS-CoV-2与其他已知引起普通感冒的冠状病毒（229 E，OC 43，NL 63和HKU 1）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。肺炎和呼吸衰竭是报告的感染这些冠状病毒的临床并发症。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，包括重新利用临床批准的针对SARS-CoV-2细胞进入和复制的药物。例如，病毒聚合酶已经是主要的治疗靶标，如在靶向各种病毒病原体（例如，HIV 1、HCV和HBV）。事实上，埃默里大学药物发现中心（CDD）的化学小组（由R。F. Schinazi），先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（3 TC）和恩曲他滨（FTC）治疗HIV，以及索非布韦治愈HCV。基于这一成功的机制策略，我们目前针对SARS-CoV-2的战略方法是用可能抑制病毒复制的特异性核苷化合物靶向其病毒RNA依赖性RNA聚合酶。在这个竞争性的修订申请中，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聚合酶抑制剂库，它由200种化合物组成。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特征，该试验由一组关键细胞系（包括人原代细胞）组成。我们的目标是研究这些化合物中的每一种的抗病毒功效，通过采用我们建立的体外SARS-CoV-2病毒培养和病毒检测系统。