A new synergy for flavivirus therapy: RNAi enhancement and viral mutagens

黄病毒治疗的新协同作用：RNAi 增强和病毒诱变剂

基本信息

批准号：
8190923
负责人：
JEFFREY B ARTERBURN
金额：
$ 17.75万
依托单位：
NEW MEXICO STATE UNIVERSITY LAS CRUCES
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-06-01 至 2013-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8190923
关键词：
Antibiotics Antiviral Agents Antiviral Therapy Base Sequence Binding Biological Assay Cells Ciprofloxacin Cleaved cell Clinical Combined Modality Therapy Complementary DNA Dengue Dengue Hemorrhagic Fever Dengue Virus Development Disease Dose Double-Stranded RNA Drug Combinations Drug Interactions Entropy Enzymes Eukaryota Exhibits FDA approved Failure Flavivirus Flavivirus Infections Fluoroquinolones Genome Genomics Human In Vitro Incidence Individual Length Licensing Measures Minor Mutagenesis Mutagens Mutation Parents Pathway interactions Pharmaceutical Preparations RNA Interference RNA Interference Pathway RNA Viruses Regimen Relative (related person)Reporter Research Resistance Ribavirin Risk Role Serotyping Severity of illness Small Interfering RNA Sum Testing Therapeutic Tick-Borne Encephalitis Virus Tick-Borne Encephalitis Viruses Toxic effect Vaccines Viral Viral Genome Virus Virus Replication West Nile virus Yellow Fever base burden of illness design drug development flasks global health improved in vivo innovation killings mutant novel nucleoside analog pathogen pressure research study trend vector control virus culture

项目摘要

DESCRIPTION (provided by applicant): The genus Flavivirus, comprising 80 species of single-stranded, positive-sense RNA viruses, includes a large number of globally significant emerging pathogens. In the last 50 years many flaviviruses, such as dengue, West Nile, and tick-borne encephalitis viruses, have exhibited dramatic increases in incidence, disease severity and/or geographic range. For example the annual number of cases of dengue hemorrhagic fever cases worldwide has risen from nearly 0 in the 1950's to 500,000 today. These trends are exacerbated by failure of vector control to limit virus spread as well as the absence of vaccines for viruses such as dengue and West Nile. Thus effective antiviral therapies are urgently needed to ameliorate the disease burden imposed by flaviviruses. At present, however, no licensed therapies are available for any flavivirus, largely because existing broad-spectrum drugs have failed to show efficacy against flaviviruses or have generated unacceptably high levels of toxicity. To overcome these limitations, it will be necessary to develop not only new antiviral drugs but also innovative strategies to lower their effective dose and thereby mitigate toxicity. The recent discovery that certain FDA-approved fluoroquinolone antibiotics enhance the activity of the RNA interference pathway suggests one promising new strategy. RNA interference is a ubiquitious antiviral defense of eukaryotes that acts by targeting small interfering RNA's (siRNA's) to complementary regions in the viral genome; genomes bound to siRNA's are marked for cleavage and degradation. Because binding of siRNA's to a target sequence requires nearly perfect complementarity, RNAi imposes selection pressure for viral mutation that disrupts such complementarity. The proposed research will test the hypothesis that enhancing RNAi will amplify the effect of mutagenic nucleoside analogs on dengue virus mutation rate and replication, and that the synergistic effect of RNAi enhancement will accelerate lethal mutagenesis driven by nucleoside analogs. If this hypothesis is correct, the finding of this study will represent a significant advance in the development of new therapies for flaviviral disease. PUBLIC HEALTH RELEVANCE: Flaviviruses like dengue, West Nile and yellow fever sicken and kill millions of people worldwide each year, but at present there are no antiviral drugs available to treat a flavivirus infection. The proposed research will test whether a novel combination of drugs offers a new potential treatment for flaviviruses.

描述（由申请人提供）：黄病毒属由 80 种单链正义 RNA 病毒组成，包括大量全球重要的新兴病原体。在过去 50 年中，许多黄病毒，例如登革热病毒、西尼罗河病毒和蜱传脑炎病毒，在发病率、疾病严重程度和/或地理范围方面都表现出急剧增加。例如，全世界每年的登革出血热病例数已从 1950 年代的近 0 例上升到今天的 50 万例。由于未能通过病媒控制来限制病毒传播，以及缺乏针对登革热和西尼罗河病毒等病毒的疫苗，加剧了这些趋势。因此，迫切需要有效的抗病毒疗法来减轻黄病毒造成的疾病负担。然而，目前还没有针对任何黄病毒的许可疗法，主要是因为现有的广谱药物未能显示出针对黄病毒的功效或产生了令人无法接受的高水平毒性。为了克服这些限制，不仅需要开发新的抗病毒药物，还需要开发创新策略来降低其有效剂量，从而减轻毒性。最近发现 FDA 批准的某些氟喹诺酮类抗生素可增强 RNA 干扰途径的活性，这表明了一种有前景的新策略。 RNA 干扰是真核生物普遍存在的抗病毒防御机制，通过将小干扰 RNA (siRNA) 靶向病毒基因组中的互补区域来发挥作用；与 siRNA 结合的基因组被标记为裂解和降解。由于 siRNA 与靶序列的结合需要近乎完美的互补性，因此 RNAi 对破坏这种互补性的病毒突变施加了选择压力。拟议的研究将检验以下假设：增强RNAi将放大诱变核苷类似物对登革热病毒突变率和复制的影响，并且RNAi增强的协同效应将加速核苷类似物驱动的致死诱变。如果这一假设正确，这项研究的发现将代表黄病毒疾病新疗法开发的重大进展。公共卫生相关性：登革热、西尼罗河和黄热病等黄病毒每年导致全世界数百万人患病并死亡，但目前尚无抗病毒药物可用于治疗黄病毒感染。拟议的研究将测试一种新型药物组合是否为黄病毒提供新的潜在治疗方法。