T-705 Pyrazine derivative treatment of highly pathogenic arenaviral infections

T-705吡嗪衍生物治疗高致病性沙病毒感染

• 批准号: 8261429
• 负责人: Brian B. Gowen
• 金额: $ 31.32万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8261429
• 关键词: Address; Adsorption; Advanced Development; Africa; American Hemorrhagic Fever; Animal Model; Animals; Antiviral Agents; Antiviral Therapy; Arenavirus; Biodistribution; Biological Assay; Bolivian Hemorrhagic Fever Virus; Categories; Cavia; Cessation of life; Chemicals; Clinical Trials; Containment; Data; Development; Disease; Drug Delivery Systems; Drug Kinetics; Drug or chemical Tissue Distribution; Eating; Excretory function; Goals; Guanarito virus; Hamsters; Human; Infection; Influenza; Japan; Junin virus; Lassa Fever; Lassa virus; Licensing; Metabolism; Modeling; National Institute of Allergy and Infectious Disease; Nucleosides; Nucleotides; Partner in relationship; Pharmacology; Pichinde virus; Polymerase; Pyrazines; RNA; RNA Viruses; RNA-Directed RNA Polymerase; Renal function; Replicon; Research; Research Project Grants; Resistance; Ribavirin; Safety; South America; South American; Staging; Tacaribe Complex Viruses; Therapeutic; Time; Toxic effect; Treatment Protocols; Viral; Viral Hemorrhagic Fevers; Viral Load result; Virus; Virus Diseases; base; biodefense; human disease; influenzavirus; nonhuman primate; nucleoside analog; pathogen; prevent; programs; research study; success

Several arenaviruses cause hemorrhagic fever others) and Africa (Lassa virus), and are classil antiviral with activity against these agents, riba\ infections and has significant toxicity. The Toya 705, with broad -spectrum activity against a nun 705 prevents death in the Pichinde virus (PICV initiated at late stages of infection. T-705 is cur influenza virus infections, so the safety of the c goal of this project is to advance the developrm facilitated by the completion of the following spi dependent RNA-oolvmerase (RdRp) is the prirr Program Director (Last, First, Middle): Belisle, John T. (HF) in endemic regions of South America (Junin virus and fied as Category A pathogens by the NIAID. The only licensed /irin, has had mixed success in the treatment of severe ma Chemical Co. has developed a pyrazine derivative, Tnber of RNA viruses, including arenaviruses. Remarkably, T- ) hamster model of arenaviral HF even when treatment is rently in clinical trials in the US and Japan for the treatment of ompound is being comprehensively addressed. The long-term ;nt of T-705 for the treatment of arenaviral HFs. This will be scific aims. 1. Determine if the inhibition of the RNAiarv T-705 mechanism of action aqainst arenaviruses. T-705 acts as a nucleoside analog specifically inhibiting the influenza polymerase. RdRp domains are attractive drug targets since they are not present in the host and are conserved among RNA viruses. Several strategies will be used to investigate the RdRp of the arenaviruses as the main target of T-705 inhibition, including time-of-addition and nucleotide/nucleoside competition studies, replicon-based inhibition assays and the examination of resistant viruses. 2. Determine T-705 distribution and pharmacokinetics (PK) during advanced PICV infection in hamsters and efficacv in the auinea piq (GP) PICV infection model. Tissue distribution and PK will be determined in infects infection can diminish kidney function, altering experiments in PICV-challenged GPs will facilit to the more costly Junin virus (JUNV) GP effice nonhuman primate models of JUNV infection. F demonstrable efficacy in GP and nonhuman pr agents, which more faithfully model human dise Research Focus on Viral Therapeutics, and wil }d and uninfected hamsters since pantropic arenaviral normal biodistribution and PK profiles. T-705 efficacy ate the selection of optimal treatment regimens for transition cv studies. 3. Evaluate the efficacv of T-705 in GP and :DA approval for use against arenaviral HF agents will require mate models based on infection with authentic arenaviral HF jase. This research project fits within the RMRCE Integrated interact directly with RPs 3.1, 3.4, 3.6, and 3.7.

几种新城疫病毒可引起出血热 其他)和非洲(拉萨病毒)，并被归类 具有抗病毒活性的药物，RIBA 感染，并有显著毒性。托亚 705，针对修女的广谱活动 705预防皮钦德病毒(PICV)死亡 在感染后期就开始了。T-705已修复 流感病毒感染，所以丙型流感的安全性 该项目的目标是推动 通过完成以下SPI提供帮助 依赖的RNA卵聚酶(RdRp)是 项目总监(最后、第一、中间)：Belisle，John T. (出血热)南美洲流行地区(Junin病毒和 被NIAID鉴定为A类病原体。唯一获得许可的 /IRIN，在治疗重症肺炎方面取得了好坏参半的结果 马化工公司开发了一种吡嗪衍生物，Tnber 核糖核酸病毒，包括阿拉伯病毒。值得注意的是，T- )即使治疗是ArenaVirus HF的仓鼠模型 目前正在美国和日本进行临床试验，用于治疗 庞氏综合症正在得到全面解决。长期的 T-705的NT治疗肾综合征出血热。这将是 科学的目标。1.确定RNAiarv的抑制是否 T-705对病毒的作用机制。T-705 作为一种核苷类似物，专门抑制流感聚合酶。RdRp域很有吸引力 药物靶标，因为它们不存在于宿主中，并且在RNA病毒中保守。几个 将使用策略来研究作为T-705抑制的主要靶点的ArenaVirus的RdRp， 包括添加时间和核苷酸/核苷竞争研究、基于复制子的抑制分析 以及耐药病毒的检测。2.测定T-705在人体内的分布和药代动力学 金黄地鼠晚期猪圆环病毒感染及猪圆环病毒感染模型的有效性。组织 分布和PK将在感染中确定 感染会削弱肾功能，改变 在PICV挑战的全科医生中的实验将使它变得容易 对成本更高的Junin病毒(JUNV)GP的影响 JUNV感染的非人灵长类动物模型。F 在全科医生和非人类媒体上表现出明显的疗效 更忠实地模拟人类疾病的代理 专注于病毒治疗的研究，并将 *d和未感染的仓鼠自泛热带狂犬病病毒 正态生物分布和PK谱。T-705药效 过渡时期最佳治疗方案的选择 简历研究。3.评价T-705治疗前列腺癌和前列腺癌的疗效。 ：DA批准用于对抗ArenaVirus HF试剂将需要 基于感染正宗阿雷诺病毒HF的交配模型 杰斯。本研究项目适用于RMRCE集成 直接与RPS 3.1、3.4、3.6和3.7交互。