New Inhibitors of HIV latency reactivation

摘要 公司-Ithax Pharmtics是一家新剥离出来的生物技术公司，位于西雅图，专注于 开发以RNA为靶标的专利小分子化学。它的创始人的经验跨越了病毒学， 药物设计和RNA的结构和功能，并使其在RNA靶向方面具有独特的技术专长 太空。他们的商业专长包括成功创建并随后出售RiboTarget，以及 1997-2001年在英国剑桥成立了一家专注于RNA的小分子药物发现公司。这是第一阶段的STTR Proposal列出了一系列超出学术发现范围的实验，这些实验对推进 并降低公司的商业化和制药计划的风险。成功完成这项工作 该项目将帮助Ithax提高激动型先导化合物的功效，验证其在相关初级 细胞模型系统，并获得ADME和PK/PD数据。由此产生的进展将促进其商业 通过提供所需的数据来启动其铅小分子的临床前开发 随后的第二阶段SBIR项目，以及获得促进可持续发展研究所需的私人资本 这将随之而来。 技术-存在潜伏但具有复制能力的病毒，主要驻留在非常小的 静息记忆的CD4T细胞群体限制了抗逆转录病毒治疗的长期疗效，因为 一旦暂停治疗，病毒不可避免地会反弹。逃避潜伏期是由转录驱动的 重新激活HIV前病毒，这需要宿主P-TEFb激酶刺激RNA Pol II的处理能力， 它通过与病毒Tat蛋白的相互作用被招募到HIV TAR RNA中，Tat蛋白是唯一转录的 由病毒编码的激活器。因此，抑制TAT-TAR-P-TEFb复合体将导致 抑制病毒重新激活，防止病毒从潜伏期出现。这个项目进一步推动了 该公司发现的一类新的TAT-TAR-P-TEFb小分子抑制剂的开发 与TAR RNA相互作用并抑制细胞内病毒复制的创始人。它将优化生物化学和生物化学 使用基于结构的药物设计对铅的细胞效力；评估铅的药理性质 体外和体内药代动力学和毒性，并评价其活性和作用机制 复杂的延迟细胞模型。收集这些数据将允许随后提交强有力的 第二阶段SBIR项目侧重于临床前研究，并同时寻求所需的私人资本 用于支持IND的研究。 1

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