Develop Potent Methyltransferase Inhibitors to Target Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)

开发有效的甲基转移酶抑制剂来治疗严重急性呼吸系统综合症冠状病毒 2 (SARS-CoV-2)

• 批准号: 10175592
• 负责人: Y. George Zheng
• 金额: $ 41.53万
• 依托单位: UNIVERSITY OF GEORGIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10175592
• 关键词: 2019-nCoV; Affinity; Antiviral Agents; Binding; Biochemical; Biological Assay; COVID-19; COVID-19 pandemic; Cell model; Cells; Cellular Assay; Centers for Disease Control and Prevention (U.S.); Cessation of life; Chemicals; China; Clinical; Clinical assessments; Collection; Complex; Computer Assisted; Coronavirus; Coronavirus Infections; Crystallization; DNA Sequence; DNA-Directed RNA Polymerase; Databases; Development; Disease Outbreaks; Docking; Drug Targeting; Enzymes; Escherichia coli; Etiology; Event; Family; Future; Genome; Hong Kong; Human; Immune; Immune system; Investigational Therapies; Lead; Life; Ligand Binding; Measures; Methods; Methylation; Methyltransferase; Neutral Red; Nickel; Nonstructural Protein; Outcome; Pathway interactions; Peptide Hydrolases; Pharmaceutical Preparations; Population; Positioning Attribute; Prevention; Proteins; RNA; RNA Caps; RNA Viruses; Recombinants; Reporting; Research; Resolution; Ribose; Roentgen Rays; SARS coronavirus; Severe Acute Respiratory Syndrome; Source; Speed; Stains; Structure; Testing; Therapeutic; Therapeutic Agents; United States; Validation; Viral; Viral Vaccines; Virulence; Virus; Virus Diseases; Virus Replication; Work; base; betacoronavirus; combat; design; drug discovery; effective therapy; enzyme mechanism; experience; expression vector; in silico; in vivo Model; inhibitor/antagonist; innovation; novel; novel therapeutics; pandemic disease; pathogen; pre-clinical assessment; protein complex; screening; small molecule libraries; targeted treatment; therapeutically effective; viral RNA; virtual screening

The recently emerged coronavirus disease-2019 (COVID-19) that commenced in Wuhan China has spread globally at an unprecedented speed. The etiological pathogen for this pandemic disease is a new, enveloped, positive-sense, single-stranded RNA coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS- CoV-2). The genome of SARS-CoV-2 is evolutionarily related to the betacoronavirus that caused the SARS outbreak in 2003. Currently there are no targeted effective therapeutics and no vaccines for the viral prevention. In order to rapidly innovate effective medications for clinical curing of this viral infection, we are launching a drug discovery campaign with combined team efforts to develop new therapeutic agents against COVID-19. We aim to target the nonstructural protein 16 (nsp16) of SARS-CoV-2, the ribose 2′-O-methyltransferase enzyme (2′-O- MTase) that is responsible for the formation of viral RNA cap-1 structure, the last step of the 5’-capping of the coronavirus. The methylation mechanism is important for both viral replication and viral evasion by host immune recognition. Thus, drugs targeting the 5’-capping pathway are ideal for eliminating the virulence of this pathogen. The X-ray crystal structures of nsp16/nsp10 protein complex of SARS-CoV-2 have recently been resolved, which showed a great structural similarity to the SARS-CoV nsp16/nsp10 complex structures. The availability of these high-resolution structures provide the important structural basis for screening and design of nsp16 inhibitors. In this project, we will combine computer-aided in silico screening, sensitive biochemical assays, and antiviral cell assays to identify potent nsp16 inhibitors to combat this coronavirus. We will carry out structure-based high- throughput virtual screening to rapidly discover effective inhibitors of the nsp16 2’-O-MTase. The top screening hits will be subjected to biochemical screening against recombinant nsp16 enzyme of SARS-COV-2. Validated nsp16 2’-O-MTase inhibitors will be tested for antiviral activity against SARS-CoV2 strains. The accomplishment of this drug discovery campaign is to generate a novel avenue of experimental therapy against the existential COVID-19 pandemic via inhibiting the 5’-capping pathway of the coronavirus.

最近出现的 2019 冠状病毒病 (COVID-19) 在中国武汉开始传播 以前所未有的速度席卷全球。这种大流行病的病原体是一种新的、有包膜的、 正链单链 RNA 冠状病毒、严重急性呼吸综合征冠状病毒 2（SARS- 冠状病毒-2）。 SARS-CoV-2 的基因组在进化上与引起 SARS 的 β 冠状病毒相关 2003年爆发疫情。目前尚无针对性的有效治疗方法，也没有预防病毒的疫苗。 为了快速创新临床治疗这种病毒感染的有效药物，我们正在推出一种药物 发现活动与团队共同努力开发针对 COVID-19 的新治疗药物。我们的目标 靶向 SARS-CoV-2 的非结构蛋白 16 (nsp16)，即核糖 2′-O-甲基转移酶 (2′-O- MTase）负责形成病毒 RNA cap-1 结构，这是病毒 5’ 加帽的最后一步 新冠病毒。甲基化机制对于病毒复制和宿主免疫的病毒逃避都很重要 认出。因此，针对 5'-加帽途径的药物是消除这种病原体毒力的理想选择。 SARS-CoV-2的nsp16/nsp10蛋白复合物的X射线晶体结构最近已被解析， 与 SARS-CoV nsp16/nsp10 复合体结构表现出极大的结构相似性。这些的可用性 高分辨率结构为nsp16抑制剂的筛选和设计提供了重要的结构基础。在 在这个项目中，我们将结合计算机辅助计算机筛选、敏感生化检测和抗病毒细胞 鉴定有效的 nsp16 抑制剂来对抗这种冠状病毒的测定。我们将开展基于结构的高 通量虚拟筛选，快速发现 nsp16 2'-O-MTase 的有效抑制剂。顶级筛选 对SARS-COV-2的重组nsp16酶进行生化筛选。已验证 nsp16 2’-O-MTase 抑制剂将测试针对 SARS-CoV2 菌株的抗病毒活性。成就 这项药物发现活动的目的是创造一种针对存在主义的实验疗法的新途径 COVID-19 通过抑制冠状病毒的 5' 加帽途径而大流行。