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.

最近出现的冠状病毒疾病 - 2019年（19号）在武汉中国蔓延开来 以前所未有的速度在全球范围内。这种大流行病的病理学是一种新的，包裹的， 阳性，单链RNA冠状病毒，严重的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造成SARS的betacoronavirus相关 2003年爆发。目前尚无有效的有效疗法，也没有用于预防病毒的疫苗。 为了快速创新这种病毒感染的临床治疗的有效药物，我们正在推出一种药物 Discovery运动通过团队合并为与Covid-19的新治疗剂共同努力。我们的目标 为了靶向SARS-COV-2的非结构蛋白16（NSP16），核糖2'-O-甲基转移酶酶（2'-O-- MTase）是导致病毒RNA CAP-1结构的形成，这是5'限制的最后一步 新冠病毒。甲基化机制对于宿主免疫的病毒复制和病毒进化都很重要 认出。这是针对5'Papping途径的药物是消除该病原体病毒的理想选择。 最近已经解决了SARS-COV-2的NSP16/NSP10蛋白复合物的X射线晶体结构 与SARS-COV NSP16/NSP10复杂结构显示出很大的结构相似性。这些的可用性 高分辨率结构为NSP16抑制剂的筛查和设计提供了重要的结构基础。在 这个项目，我们将在计算机筛选，敏感的生化测定和抗病毒细胞中结合计算机辅助 测定鉴定潜在的NSP16抑制剂以对抗该冠状病毒。我们将进行基于结构的高级 吞吐量虚拟筛选以迅速发现NSP16 2'-O-MTase的有效抑制剂。顶部筛选 对SARS-COV-2的重组NSP16酶进行生化筛选。经过验证 NSP16 2'-O-MTase抑制剂将测试针对SARS-COV2菌株的抗病毒活性。成就 这项药物发现运动是为现有的新型实验疗法途径 COVID-19通过抑制冠状病毒的5'Papping途径。