Drug Resistant HIV: Novel Target Validation and Small Molecule Lead Discovery

描述(申请人提供)：北美约有160万人感染艾滋病毒/艾滋病；全世界有3400万人。艾滋病毒/艾滋病的流行是由一种快速复制的逆转录病毒引起的，这种病毒经历了多种突变，使成功治疗变得极其困难。数百万患者的艾滋病毒毒株对目前可用的一种或多种艾滋病毒疗法具有抵抗力。全球抗击艾滋病毒/艾滋病的斗争取得了进展，但这一流行病继续在美国和世界其他地区肆虐，每年分别新增约5.1万人和250万人感染艾滋病毒。为了克服艾滋病毒的耐药性，迫切需要新的、有效的靶点和新的治疗方法。Sirga已经开发出一种新的方法，可以独特地干扰人类(宿主)细胞和艾滋病毒之间的相互作用，这对病毒的复制和传播是绝对必要的。Sirga预计这种方法将极大地降低艾滋病毒对治疗产生抗药性的可能性。使用其专有的基于机制的筛查(MBS)和HIV细胞分析，Sirga成功地识别了一组初始的生物活性靶点，这些生物活性靶点可以阻断HIV对人tRNA3Lys(HtRNA3Lys)的招募，从而启动逆转录-病毒复制的关键步骤。这些对细胞的无毒打击在剂量上对艾滋病毒有效，为发现一类新的艾滋病毒药物提供了机会。HIV对htRNA3Lys的奉献有力地证实了htRNA3Lys及其被病毒蛋白招募是抗药性可能难以实现的关键目标。在第一阶段期间 Sirga将专注于将热门歌曲转换为经过验证的、更有效力的线索。在目标1中，Sirga将使用 在硅胶和有机合成方法中，识别和选择一系列与htRNA3Lys具有更高亲和力(在NM范围内的kd)的药物类似物，如我们的MBS检测所测量的那样。在目标2中，Sirga将确定两到三个具有最佳有效无毒浓度的易处理的热门系列 在细胞分析的NM范围内。在目标3中，将确认Sirga导致明确靶向高亲和力tRNA3Lys的作用模式(MOA)和特异性。第一阶段的成功将导致第二阶段项目的重点是对主要候选者进行优化/临床前测试； 与潜在第三阶段合作伙伴的讨论正在进行中。为了补充Sirga研发团队在RNA化学和早期药物发现方面107年的集体专业知识，包括Pi Dr.Vendeix在该领域的13年和Agis顾问博士在该领域的40年任期，Sirga获得了北卡罗来纳大学艾滋病研究中心(CFAR)的纳尔逊博士的支持，Nelson博士是艾滋病毒/艾滋病方面的领先病毒学专家。高通量筛查(HTS)检测开发专家詹岑也在团队中。药物化学的努力得到了北卡罗来纳大学综合化学生物学和药物发现中心主任、前GSK全球发现药物化学副总裁弗莱博士的支持。Toone博士将从事小分子的物理有机化学研究。Dmitri Kireev博士凭借他20年的工业和学术药物发现经验，将支持这种计算方法。

DESCRIPTION (provided by applicant): Approximately 1.6 million people live with HIV/AIDS in North America; 34 million people worldwide. The HIV/AIDS epidemic is caused by a rapidly replicating retrovirus that undergoes multiple mutations, making it extremely challenging to successfully treat. Millions of patients have strains of HIV that resist one or more of the currenty available HIV therapies. Progress has been made in the global fight against HIV/AIDS, but the epidemic continues to devastate the US and the rest of the world with some 51,000 and 2.5 million new HIV infections each year, respectively. To overcome HIV's drug resistance, new, validated targets and novel therapeutics are urgently needed. Sirga has developed a novel approach that uniquely interferes with an interaction between human (the host) cells and HIV that is absolutely essential for viral replication and propagation. Sirga expects this approach to drastically reduce the potential for HIV to develop resistance to therapies. Using its proprietary mechanism- based screening (MBS) and HIV cellular assays, Sirga has successfully identified an initial set of bioactive hits that block HIV recruitment of human tRNA3Lys (htRNA3Lys), that primes reverse transcription-a critical step in viral replication. These nontoxic hits to cells at doses effective against HIV, provide an opportunity to discover a novel class of HIV drug. HIV's dedication to htRNA3Lys is a strong validation that htRNA3Lys and its recruitment by viral proteins are critical targets for which drug resistance may be difficult to achieve. During Phase I Sirga will focus on translating hits into validated and more-potent leads. In Aim 1, Sirga will use in silico and organic synthesis approaches to identify and select series of drug-like hits having higher affinity (kd in nM range) with htRNA3Lys as measured in our MBS assay. In Aim 2, Sirga will identify two to three tractable hit series having an optimum effective non-toxic concentration in the nM range in cellular assays. In Aim 3, the mode of action (MOA) and specificity of Sirga's leads to unambiguously target tRNA3Lys with high affinity will be confirmed. Phase I success will lead to a Phase II project focused on optimization/pre-clinical testing of the lead candidate; discussions with potential Phase III partners are under way. To supplement the Sirga R&D team's collective 107 years of expertise in RNA chemistry and early-stage drug discovery-including PI Dr. Vendeix's 13-year and consultant Dr. Agris' 40-year tenures in this field-Sirga has enlisted the support of Dr. Nelson of the UNC's Center for Aids Research (CFAR), a leading virology expert in HIV/AIDS. Also on the team is Mr. Janzen, a high-throughput screening (HTS) assay-development expert. The medicinal chemistry effort is supported by Dr. Frye, Director of UNC's Center for Integrative Chemical Biology and Drug Discovery and former GSK Worldwide Vice President of Discovery Medicinal Chemistry. Dr. Toone will be engaged in the physical organic chemistry of the small molecules. Dr. Dmitri Kireev, with his combined 20 years of industrial and academic drug-discovery experience, will support the computational approach.