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: 8070323
• 负责人: Brian B. Gowen
• 金额: $ 36.91万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8070323
• 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 Pharmacology; Clinical Trials; Containment; Data; Development; Disease; Drug Delivery Systems; Drug Kinetics; Drug or chemical Tissue Distribution; Eating; Excretory function; Face; 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 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; 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.

几种沙粒病毒引起出血热 其他）和非洲（拉沙病毒）， 具有抗这些药物活性的抗病毒药， 感染并具有显著的毒性。洞爷 705，对修女有广谱活性 705预防皮钦德病毒（PICV）死亡 开始于感染的晚期。T-705是曲线 流感病毒感染，所以安全的c 该项目的目标是促进发展 通过完成以下战略优先事项， 依赖性RNA聚合酶（RdRp）是主要的 节目总监（最后，第一，中间）：贝里斯，约翰T。 (HF)在南美洲流行地区（朱宁病毒和 被NIAID列为A类病原体。唯一持牌 /irin在治疗严重的 ma化学公司开发了一种吡嗪衍生物， RNA病毒，包括沙粒病毒。值得注意的是，T- ）沙粒病毒HF的仓鼠模型，即使当治疗是 目前在美国和日本进行临床试验， 目前正在全面处理这一问题。长期 T-705治疗沙粒病毒性HFs的疗效。这将是 科学的目标1.确定RNA干扰抑制是否 T-705的作用机制。T-705 作为特异性抑制流感聚合酶的核苷类似物。RdRp结构域具有吸引力 因为它们不存在于宿主中并且在RNA病毒中是保守的。几 策略将用于研究沙粒病毒的RdRp作为T-705抑制的主要靶标， 包括添加时间和核苷酸/核苷竞争研究、基于复制子的抑制测定 以及耐药病毒的检测。2.测定T-705的分布和药代动力学（PK）， 在仓鼠中晚期PICV感染和在aurepliq（GP）PICV感染模型中的效力。组织 将在感染中确定分布和PK 感染会削弱肾功能， 在PICV挑战的GP中进行的实验将有助于 到更昂贵的朱宁病毒（JUNV）GP办公室 JUNV感染的非人灵长类动物模型。F 在GP和非人PR中可证实的疗效 代理人，更忠实地模拟人类疾病， 研究重点是病毒治疗，并将 }d和未感染仓鼠，因为泛热带沙粒病毒 正常生物分布和PK特征。T-705疗效 选择最佳治疗方案， CV研究3.评价T-705治疗GP的疗效， ：DA批准用于对抗沙粒病毒HF因子将需要 基于真实沙粒病毒HF感染的交配模型 杰斯。该研究项目符合RMRCE集成 直接与RP 3.1、3.4、3.6和3.7相互作用。