New Inhibitors of HIV latency reactivation

摘要 公司- Ithax制药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来靶向RNA。其创始人的经验跨越病毒学， 药物设计和RNA结构和功能，并使其在RNA靶向方面具有独特的技术专长 空间他们的商业专长包括成功创立和随后的销售Ribotargets， 1997-2001年，在英国剑桥，专注于RNA的小分子药物发现公司。本阶段I STTR 一项提案列出了一系列实验，超出了学术发现的范围，这些实验对推进 并降低公司商业化和制药计划的风险。成功完成本 该项目将帮助Ithax提高令人兴奋的先导化合物的功效，验证其在相关主要领域的活性， 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商业化 通过提供启动其先导小分子临床前开发所需的数据， 随后的第二阶段SBIR项目，以及获得IND赋能研究所需的私人资本 那会随之而来。 技术-存在的潜伏，但复制能力的病毒主要居住在一个非常小的 静息记忆性CD 4 + T细胞群限制了抗逆转录病毒疗法的长期功效， 一旦停止治疗，病毒不可避免地会反弹。逃避潜伏期是由转录 HIV原病毒的再活化，这需要通过宿主P-TEFb激酶刺激RNA Pol II的持续合成能力， 它通过与病毒达特蛋白的相互作用而被募集到HIV TAR RNA中， 病毒编码的激活剂。由此可见，Tat-TAR-P-TEFb复合物的抑制将导致 抑制病毒再活化并防止病毒从潜伏期出现。该项目进一步推动了 开发了一种新的Tat-TAR-P-TEFb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。它将优化生物化学， 使用基于结构的药物设计的铅的细胞效能;评估铅的药理学性质， 体外和体内药代动力学和毒性，并评价其活性和作用机制 复杂的潜伏期细胞模型这些数据的收集将允许随后提交一份强有力的 第二阶段SBIR项目侧重于临床前研究，同时寻求所需的私人资本 进行IND赋能研究。 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