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.

最近在中国武汉出现的2019年冠状病毒病（COVID-19）已经蔓延 全球范围内以前所未有的速度。这种大流行病的病原体是一种新的、有包膜的、 正义单链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β冠状病毒相关 2003年爆发。目前，没有针对性的有效治疗方法，也没有用于病毒预防的疫苗。 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， 联合团队努力开发新的治疗药物来对抗COVID-19。我们的目标 针对SARS-CoV-2的非结构蛋白16（nsp 16），核糖2′-O-甲基转移酶（2′-O- MTase），其负责形成病毒RNA帽-1结构，即病毒RNA的5 '-加帽的最后一步。 冠状病毒。甲基化机制对于病毒复制和宿主免疫逃避都很重要 识别.因此，靶向5 '-加帽途径的药物是消除该病原体毒力的理想药物。 SARS-CoV-2的nsp 16/nsp 10蛋白复合物的X射线晶体结构最近已经解析， 与SARS冠状病毒nsp 16/nsp 10复合物结构相似。网站或资源的可用性 高分辨率结构为筛选和设计NSP 16抑制剂提供了重要的结构基础。在 在这个项目中，我们将结合联合收割机计算机辅助的电子筛选，敏感的生化分析， 鉴定有效的nsp 16抑制剂以对抗这种冠状病毒的试验。我们将实施基于结构的高- 通过虚拟筛选快速发现nsp 16 2 ′-O-MTase的有效抑制剂。顶级筛选 将对命中物进行针对SARS-COV-2的重组nsp 16酶的生化筛选。验证 将测试nsp 16 2 '-O-MTase抑制剂对SARS-CoV 2菌株的抗病毒活性。的完成而 这项药物发现运动的目的是创造一种新的实验疗法， 通过抑制冠状病毒的5 '-加帽途径来抑制COVID-19大流行。