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）是由严重的急性呼吸综合症冠状病毒2（SARS-COV-2）引起的新兴全球大流行。 Covid-19构成了巨大的公共卫生威胁，目前没有针对SARS-COV-2的疫苗和治疗剂。这种新型的单链包膜RNA病毒是第七个已知的人冠状病毒。 SARS-COV-2与已知引起普通感冒的其他冠状病毒不同（229E，OC43，NL63和HKU1），但与2002年的人畜共患病严重急性呼吸综合症冠状病毒和中东呼吸道综合征以及2012年的中东呼吸道综合征。尽管正在开发针对SARS-COV-2的疫苗和单克隆抗体，但目前正在考虑和测试许多研究疗法，包括针对SARS-COV-2细胞进入和复制的临床认可的临床认可的药物。例如，病毒聚合酶一直是主要的治疗靶点，如针对各种病毒病原体（例如HIV1，HCV和HBV）的多种药物发现成功所见。实际上，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）以前已经发现了几个核苷/核苷酸病毒聚合酶抑制剂，包括lamivudine（3TC）（3TC）和Emtricitabine（FTC），以治疗HIV以及Sofosbuvir to corure Hcv。在这种成功的机械策略的基础上，我们当前的SARS-COV-2战略方法是针对其病毒RNA依赖性RNA聚合酶的特定核苷化合物的靶向可能抑制病毒复制的特定核苷化合物。在此竞争性修订应用中，我们选择了一种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，该库由200种化合物组成。我们以前使用我们的体外毒性筛查测定法组成了一组由包括人类原代细胞在内的关键细胞线组成的这组化合物的安全毒性概况。我们的目标是通过采用我们已建立的体外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。