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.

几个竞技病毒引起出血热 其他）和非洲（LASSA病毒），并且是分类 抗病毒对这些药物的活性，riba \ 感染并具有明显的毒性。 TOYA 705，具有宽广的光谱活动 705防止Pichinde病毒死亡（PICV 在感染后期开始。 T-705是CUR 流感病毒感染，因此C的安全性 该项目的目标是推进开发项目 完成以下SPI的完成协助 依赖的RNA-Aoolvmerase（RDRP）是PRIRR 计划总监（最后，第一，中间）：Belisle，John T. （HF）在南美特有地区（Junin病毒和 通过NIAID作为病原体的类别。唯一的许可 /IRIN，在严重治疗方面取得了不同的成功 MA Chemical Co.已开发了吡嗪衍生物TNBER RNA病毒，包括体育症病毒。值得注意的是，t- ）Arleanviral HF的仓鼠模型，即使治疗 在美国和日本进行的临床试验中，以治疗 全面解决了混合物。长期 ; nt of t-705用于治疗支架病毒HFS。这将是 细微的目标。 1。确定RNAIARV的抑制是否 T-705作用机理AQAINST体育病毒。 T-705 充当核苷类似物，特异性抑制了流感聚合酶。 RDRP域很有吸引力 药物靶标由于它们不存在于宿主中，并且在RNA病毒中保守。一些 将使用策略来研究竞技病毒的RDRP作为T-705抑制的主要目标， 包括成熟时间和核苷酸/核苷竞争研究，基于复制子的抑制测定法 以及抗性病毒的检查。 2。确定T-705分布和药代动力学（PK） Auinea PIQ（GP）PICV感染模型中的Hamsters的晚期PICV感染和EFFICACV。组织 分布和PK将在感染中确定 感染会降低肾脏功能，改变 PICV挑战的GPS中的实验将促进 到更昂贵的Junin病毒（JUNV）GP Effice JUNV感染的非人类灵长类动物模型。 f GP和非人类PR的可证明功效 代理人，更忠实地模拟人类疾病 研究重点是病毒疗法，WIL } D和未感染的仓鼠以来 正常的生物分布和PK轮廓。 T-705功效 吃了最佳治疗方案进行过渡 简历研究。 3。评估T-705在GP和 ：DA批准用于用于针对竞技场的HF代理商 基于感染的伴侣模型，具有正宗的竞技病毒HF Jase。该研究项目符合RMRCE集成 直接与RPS 3.1、3.4、3.6和3.7互动。