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Broad Spectrum Anti-viral Compounds Targeting the SKI Complex

针对 SKI 复合物的广谱抗病毒化合物

基本信息

批准号：
10038144
负责人：
Matthew Bryan Frieman
金额：
$ 23.18万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-05 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10038144
关键词：
Affect Animal Model Antiviral Agents Binding Cell Culture Techniques Cell Nucleus Cells Chemicals Clustered Regularly Interspaced Short Palindromic Repeats Co-Immunoprecipitations Complex Computer Assisted Crystallization Cytoplasm Data Development Disease model Dose Drug Design Drug Kinetics Ebola virus Effectiveness Enzymes Family Feeds Frankfurt-Marburg Syndrome Virus Future Genes Genetic Genetic Screening Half-Life Human Hypersensitivity IRF3 gene Infection Influenza Innate Immune Response Integration Host Factors Interferons Knock-in Lead Maintenance Mammals Mediating Messenger RNA Middle East Respiratory Syndrome Coronavirus Modeling Mus Pathogenesis Pathway interactions Pattern Plasmids Process Proteins RNA RNA Binding RNA Degradation RNA metabolism Role SARS coronavirus SKI gene SKIV2L gene Signal Transduction Small Interfering RNA Structural Models System Testing Time Toxic effect Toxicology Viral Viral Proteins Virus Virus Diseases Virus Inhibitors Virus Replication Work Yeasts cytokine exosome experimental study gene discovery gene induction in silico in vitro activity in vivo in vivo Model influenzavirus interest knock-down medical countermeasure member mouse model novel pathogenic virus protein complex receptor respiratory virus response screening sensor therapeutic target viral RNA

项目摘要

Project Summary The RNA Exosome and SKI complex are major cellular machines that degrade host RNA. This machine is required for several reasons in the cell including maintenance of current RNA levels and to reduce the level of cytoplasmic RNA such that the RIGI and MDA5 sensors can detect viral RNA other than host RNA. The SKI complex was identified in a genetic screen as a host protein that interacts with both Influenza NS1 and MERS-CoV ORF4a. We were able to demonstrate that knocking down these proteins in cells caused a reduction in viral replication and an increase in Interferon stimulated gene induction, irrespective of whether a virus was there or not. The SKI complex in yeast has been crystalized and upon modeling of the human structure, we in silico identified compounds that could potentially bind to a member of the complex, WDR61. In cell culture experiments, we identified 4 compounds from the 40 identified in the modeling, that block Influenza virus, MERS-CoV and SARS-CoV replication. In this proposal, we will determine the mechanism of action of the compounds and NS1 and ORF4a on the SKI complex. We will also initiate in vivo studies to evaluate the antiviral effectiveness of the SKI targeted plasmids on Influenza virus and MERS-CoV mouse models. This work will validate a novel host target and compounds directed at the SKI complex as broadly acting antivirals.

项目摘要 RNA外泌体和SKI复合物是降解宿主RNA的主要细胞机器。这在细胞中需要机器有几个原因，包括维持当前的RNA水平并降低细胞质RNA的水平，使得RIGI和MDA 5传感器可以检测病毒 RNA不是宿主RNA。SKI复合物在遗传筛选中被鉴定为宿主蛋白与流感病毒NS 1和MERS-CoV ORF 4a相互作用。我们能够证明在细胞中敲低这些蛋白质会导致病毒复制减少，干扰素刺激基因诱导，不管是否有病毒存在。滑雪酵母中的复合物已经结晶，在模拟人体结构后，我们在计算机上鉴定了可能与复合物WDR 61的一个成员结合的化合物。在细胞培养实验中，我们从建模中确定的40种化合物中确定了4种化合物，流感病毒、MERS-CoV和SARS-CoV复制。在本建议中，我们将确定化合物和NS 1和ORF 4a对SKI复合物的作用机制。我们还将启动体内研究，以评估SKI靶向质粒对流感病毒和MERS-CoV小鼠模型。这项工作将验证一种新的宿主靶标，针对SKI复合物的化合物作为广泛作用的抗病毒药物。