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.

始于武汉的新近出现的冠状病毒病-2019年(新冠肺炎)中国现已蔓延 在全球范围内以前所未有的速度。这种大流行疾病的病原体是一种新的、包膜的、 阳性，单链RNA冠状病毒，严重急性呼吸综合征冠状病毒2(SARS- CoV-2)。SARS-CoV-2的基因组在进化上与引起SARS的贝塔冠状病毒有关 2003年暴发。目前还没有针对性的有效治疗方法，也没有预防病毒的疫苗。 为了迅速创新治疗这种病毒感染的有效药物，我们正在推出一种药物 发现活动与联合团队努力开发针对新冠肺炎的新治疗剂。我们的目标是 为了针对SARS-CoV-2的非结构蛋白16(NSP16)，核糖2‘-O-甲基转移酶(2’-O-甲基转移酶) MTase)负责病毒RNA帽-1结构的形成，这是5‘-帽的最后一步 冠状病毒。甲基化机制对病毒复制和宿主免疫逃避病毒都很重要。 承认。因此，针对5‘-封顶途径的药物是消除这种病原体毒力的理想药物。 SARS-CoV-2的nsp16/nsp10蛋白复合体的X射线晶体结构最近得到了解析， 与SARS-CoV nsp16/nsp10复合结构有很大的相似性。这些产品的可用性 高分辨结构为nsp16抑制剂的筛选和设计提供了重要的结构基础。在……里面 在这个项目中，我们将结合计算机辅助的电子筛查、灵敏的生化分析和抗病毒细胞 检测以确定有效的nsp16抑制剂来对抗这种冠状病毒。我们将开展以结构为基础的高增长 通过虚拟筛选快速发现有效的nsp16 2‘-O-MTase抑制剂。最热门的放映 HITS将接受针对SARS-COV-2重组nsp16酶的生化筛选。经过验证 NSP16 2‘-O-MTase抑制剂将被测试对SARS-CoV2毒株的抗病毒活性。成就 这场药物发现运动的目的是产生一种对抗存在主义的实验性治疗的新途径 通过抑制冠状病毒的5‘端封顶途径，新冠肺炎大流行。