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Mechanism of RVFV nucleocapsid targeting drugs

RVFV核衣壳靶向药物作用机制

基本信息

批准号：
8626532
负责人：
J. Stephen Lodmell
金额：
$ 43.24万
依托单位：
UNIVERSITY OF MONTANA
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-15 至 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8626532
关键词：
Affect Affinity Africa Africa South of the Sahara Agriculture Amino Acids Animals Antiviral Agents Binding Binding Sites Biochemical Biochemical Genetics Biological Assay Biological Factors Categories Cell Culture Techniques Centers for Disease Control and Prevention (U.S.)Cessation of life Charge Chemicals Cleaved cell Complex Culicidae DNA Sequence Rearrangement Disease Drug Targeting Electrophoretic Mobility Shift Assay Exhibits Gel Chromatography Generic Drugs Genetic Genomics Geographic Locations Goals Growth Health Human Infectious Agent Kinetics Label Laboratories Libraries Licensing Life Cycle Stages Ligands Light Livestock Measurable Measures Molecular Mechanisms of Action Molecular Target Molecular Virology Monitor Mutation Analysis North America Nucleocapsid Nucleocapsid Proteins Pattern Pharmaceutical Preparations Pharmacotherapy Preclinical Drug Evaluation Proteins RNA RNA Binding RNA Sequences Research Rift Valley fever virus Risk Science Structure Symptoms Testing Training Vaccines Viral Viral Hemorrhagic Fevers Virus Virus Diseases Virus Replication Work abortion climate change combat drug development flu graduate student high throughput screening inhibitor/antagonist insight juvenile animal medical schools monomer mutant novel pathogen pregnant prototype public health relevance research study resistance mutation stoichiometry stopped-flow fluorescence time interval undergraduate student vector mosquito viral RNA

项目摘要

DESCRIPTION (provided by applicant): Rift Valley fever virus (RVFV) is a mosquito-borne emerging infectious agent with potential for major impacts on human and agricultural animal health. It is a CDC/USDA Category A Select Agent, and has been recognized by the World Organization for Animal Health as a high consequence pathogen with potential for global spread. There are no proven treatments for RVFV infections and there is no licensed vaccine that has been proven safe and effective. We recently identified 78 compounds in a novel molecular target high throughput screen that interfere with the interaction of RVFV nucleocapsid protein, N, and a target RNA. These compounds come from existing drug and drug-like molecule libraries and several of the compounds show measurable inhibition of RVFV replication in cell culture. We propose to ascertain the molecular mechanism of action of several of the most promising compounds. We will use biochemical, biophysical and genetic approaches to determine the binding site(s) for the compounds on N and we will determine whether they inhibit the specific RNA binding activity or the generic RNA binding activity that are both intrinsic to N. Specifically, we will determine whether the inhibitory compounds interfere directly with RNA binding, interfere with nucleocapsid protein oligomerization, or have a target that is distinct from either the RNA-protein or protein-protein interfaces using RNA and drug binding assays with wild-type and mutant nucleocapsid protein. The research promises benefits to the fields of biomedicine and agricultural science by expanding our understanding of virus growth and inhibition, and by making advances toward new drug therapies to combat RVFV infections.

描述（由申请人提供）：裂谷热病毒（RVFV）是一种由蚊子传播的新兴传染原，可能对人类和农业动物健康产生重大影响。它是 CDC/USDA A 类精选病原体，并已被世界动物卫生组织认定为具有全球传播潜力的高后果病原体。对于 RVFV 感染，尚无行之有效的治疗方法，也没有已被证明安全有效的许可疫苗。我们最近在新型分子靶标高通量筛选中鉴定出了 78 种化合物，这些化合物干扰 RVFV 核衣壳蛋白、N 和靶标 RNA 的相互作用。这些化合物来自现有的药物和类药物分子库，其中几种化合物在细胞培养物中显示出对 RVFV 复制的可测量抑制作用。我们建议确定几种最有前途的化合物的分子作用机制。我们将使用生物化学、生物物理和遗传学方法来确定 N 上化合物的结合位点，并确定它们是否抑制特定 RNA 结合活性或通用 RNA 结合活性。具体而言，我们将使用野生型和突变型核衣壳蛋白进行 RNA 和药物结合测定，确定抑制性化合物是否直接干扰 RNA 结合、干扰核衣壳蛋白寡聚化，或者具有与 RNA-蛋白或蛋白-蛋白界面不同的靶标。这项研究有望扩大我们对病毒生长和抑制的了解，并在对抗 RVFV 感染的新药物疗法方面取得进展，从而为生物医学和农业科学领域带来好处。