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

基本信息

批准号：
7675648
负责人：
Brian B. Gowen
金额：
$ 31.03万
依托单位：
COLORADO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-05-01 至 2014-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7675648
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 biodefense human disease influenzavirus nonhuman primate nucleoside analog pathogen prevent programs research study success

项目摘要

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），并且是经典的具有对抗这些药物活性的抗病毒药物，riba\ 感染并具有显着的毒性。洞爷 705，针对修女的广谱活动 705 可预防皮钦德病毒（PICV 在感染晚期开始。 T-705 已上市流感病毒感染，所以c的安全性该项目的目标是促进开发人员通过完成以下 spi 来促进依赖的 RNA 聚合酶 (RdRp) 是主要的项目总监（最后、第一、中间）：Belisle, John T. (HF) 南美洲流行地区（胡宁病毒和被NIAID列为A类病原体。唯一获得许可的 /irin，在治疗严重疾病方面取得了不同程度的成功马化工开发出吡嗪衍生物Tnber RNA病毒，包括沙粒病毒。值得注意的是，T- ) 沙粒病毒性心力衰竭的仓鼠模型，即使治疗是目前正在美国和日本进行临床试验，用于治疗问题正在得到全面解决。长期来看 T-705 用于治疗沙粒病毒性 HF 的 nt。这将是科学目标。 1. 确定RNAiarv是否受到抑制 T-705 的作用机制针对沙粒病毒。 T-705 作为核苷类似物，特异性抑制流感聚合酶。 RdRp 域很有吸引力药物靶点，因为它们不存在于宿主体内并且在 RNA 病毒中是保守的。一些将使用策略来研究沙粒病毒的 RdRp 作为 T-705 抑制的主要目标，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查。 2. 确定 T-705 分布和药代动力学 (PK) 仓鼠的晚期 PICV 感染及其在 ainea piq (GP) PICV 感染模型中的功效。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 GP 中进行的实验将有助于更昂贵的胡宁病毒（JUNV）GP效果 JUNV 感染的非人灵长类动物模型。 F 在全科医生和非人类公关中具有明显的功效代理，更忠实地模拟人类疾病研究重点是病毒治疗，并将 }d 和自泛热带沙粒病毒以来未感染的仓鼠正常的生物分布和 PK 特征。 T-705功效选择最佳过渡治疗方案简历研究。 3.评估T-705在GP中的疗效和：DA 需要批准用于对抗沙病毒性 HF 药物基于真实沙病毒 HF 感染的交配模型杰斯。该研究项目属于 RMRCE 综合研究项目直接与 RP 3.1、3.4、3.6 和 3.7 交互。