New Inhibitors of HIV latency reactivation

HIV潜伏期再激活的新抑制剂

基本信息

批准号：
10208701
负责人：
JONATHAN KARN
金额：
$ 29.84万
依托单位：
ITHAX PHARMACEUTICALS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-02 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10208701
关键词：
Academia Advocate Affinity Animals Anti-Retroviral Agents Antiviral Agents Binding Biochemical Biological Assay Biological Models Biotechnology CD4 Positive T Lymphocytes Capital Cell Line Cell Membrane Permeability Cell model Cells Chemistry Complex DNA Polymerase II DNA-Directed RNA Polymerase Data Data Collection Development Disclosure Disease remission Drug Design Drug Kinetics Drug Targeting England Funding Genetic Transcription Goals Growth HIV HIV Genome In Vitro Industry Infection Lead Legal patent Licensing Modeling Molecular Patients Penetration Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacologic Substance Pharmacology Phase Phosphotransferases Population Positioning Attribute Positive Transcriptional Elongation Factor B Privatization Property Proviruses RNA Regimen Reporting Rest Risk Safety Sales Series Small Business Innovation Research Grant Small Business Technology Transfer Research Structure Suspensions Technical Expertise Technology Therapeutic Agents Toxic effect Transcription Coactivator Transcription Elongation Treatment Protocols Universities Viral Viral Physiology Viremia Virus Virus Inhibitors Virus Latency Virus Replication Washington antiretroviral therapy base clinical investigation commercialization design drug discovery experience experimental study improved in vivo inhibitor/antagonist latent HIV reservoir memory CD4 T lymphocyte novel strategies pharmacokinetics and pharmacodynamics pre-clinical preclinical development premature prevent reactivation from latency recruit small molecule small molecule inhibitor tat Protein three dimensional structure virology

项目摘要

ABSTRACT Company - Ithax Pharmaceutical is a new spin-off biotechnology company, located in Seattle, focused on developing proprietary small molecule chemistry to target RNA. The experience of its founders spans virology, drug design and RNA structure and function, and gives it a unique technological expertise in the RNA-targeting space. Their commercial expertise includes the successful founding, and subsequent sale, of Ribotargets, an RNA-focused small molecule drug discovery company in Cambridge, England in 1997-2001. This Phase I STTR proposal lays out a series of experiments, beyond the scope of academic discovery, that are critical to advance and de-risk the commercialization and pharmaceutical plans of the company. Successful completion of this project will help Ithax improve the efficacy of exciting lead compounds, validate their activity in relevant primary cell model systems, and obtain ADME and PK/PD data. The resulting progress would facilitate its commercial growth by providing the data required to initiating the pre-clinical development of its lead small molecules under a subsequent phase II SBIR project, and the acquisition of the private capital required for IND-enabling studies that will follow. Technology – The existence of latent but replication competent viruses residing primarily in a very small population of resting memory CD4+ T cells limits the long term efficacy of anti-retroviral therapy because the virus inevitably rebounds once therapy is suspended. Escape from latency is driven by transcriptional reactivation of the HIV provirus, which requires stimulation of RNA Pol II processivity by the host P-TEFb kinase, which is recruited to the HIV TAR RNA through its interaction with the viral Tat protein, the only transcriptional activator encoded by the virus. It follows that inhibition of the Tat-TAR-P-TEFb complex would lead to suppression of viral reactivation and prevents the virus emergence from latency. This project furthers the development of a new class of small molecule inhibitors of Tat-TAR-P-TEFb discovered by the company’s founders that interact with TAR RNA and inhibit viral replication in cells. It will optimize the biochemical and cellular potency of the lead using structure-based drug design; assess the lead’s pharmacological properties in vitro and its in vivo pharmacokinetics and toxicity and evaluate its activity and mechanism of action in sophisticated cellular models of latency. Collection of these data will allow subsequent submission of a strong phase II SBIR project focused on pre-clinical investigations, and the parallel pursuit of private capital required for IND-enabling studies. 1

抽象的公司 - Ithax Pharmaceutical是一家新的分拆生物技术公司，位于西雅图，专注于开发专有的小分子化学以靶向RNA。其创始人的经验跨越病毒学，药物设计和RNA的结构和功能，并在RNA靶向方面具有独特的技术专长空间。他们的商业专业知识包括Ribotargets的成功建立和后续出售， 1997 - 2001年，英格兰剑桥市以RNA为重点的小分子药物发现公司。这个阶段我sttr 提案提出了一系列实验，超出了学术发现的范围，这些实验对于进步至关重要并降低公司的商业化和药品计划。成功完成项目将帮助ITHAX提高令人兴奋的铅化合物的效率，验证其在相关初级的活动细胞模型系统，并获得ADME和PK/PD数据。由此产生的进展将有助于其广告通过提供启动其铅小分子临床前开发所需的数据来增长随后的II阶段SBIR项目，并收购了辅助研究所需的私人资本那将随之而来。技术 - 潜在但复制能胜任的病毒的存在，主要居住在很小的地方静息记忆CD4+ T细胞的种群限制了抗逆转录病毒疗法的长期效率，因为一旦治疗暂停，病毒就不可避免地反弹。逃避潜伏期是由转录驱动的 HIV病毒的重新激活，它需要宿主P-TEFB激酶刺激RNA POL II的加工性通过与病毒TAT蛋白的相互作用将其募集到HIV TAR RNA，这是唯一的转录由病毒编码的激活剂。因此，抑制TAT-TAR-P-TEFB复合物将导致抑制病毒重新激活并防止病毒出现潜伏期。这个项目进一步开发公司的TAT-P-TEFB的新型小分子抑制剂与TAR RNA相互作用并抑制细胞中病毒复制的创始人。它将优化生化和使用基于结构的药物设计的铅的细胞效力；评估铅的药物特性体内药代动力学和毒性，并评估其活性和作用机理延迟的复杂细胞模型。这些数据的收集将允许随后提交强大第二阶段SBIR项目的重点是临床前调查，以及对私有资本的平行追求用于辅助研究。 1