Integrative approach for accelerating filarial worm drug discovery to treat river blindness

摘要 河盲症(盘尾丝虫病)是一种主要的被忽视的慢性热带疾病，已被世界卫生组织 世卫组织要求到2030年消除。目前，国际控制程序试图中断传输 在成虫10-14年的生命周期内，每年大规模给药(MDA)感染，使用 伊维菌素是一种杀灭螺旋体丝虫的微丝虫药物，是引起螺旋体丝虫病的病原体。 盘尾丝虫病。然而，丙二醛和伊维菌素在非洲被混淆了，因为它不能在联合使用的地区使用。 由于有发生严重不良事件的风险而导致的地方性血吸虫病。我们项目的总体目标是开发一部小说 直接大杀丝虫(直接致死成虫)临床前候选药物作为靶向治疗 使用多维跨学科实验方法研究盘尾丝虫病。 我们的建议基于我们已经建立的两个主要资源：a)广泛的组学资源， 允许在成虫中识别确定的保守的和多样化的基本分子靶标， 以及b)多方面筛选漏斗，其被成功地用于体外筛选 批准临床使用的药物，从而鉴定出具有大杀丝活性的药物。在硅胶中 优先次序与对抗成虫阶段有效的药物的实验鉴定相结合 丝虫线虫导致具有已知药物适应症和假定靶标适应症的抑制剂的短名单 对，为我们合理优化具有直接大杀丝潜力的新化合物奠定了基础。 因此，我们提出的目标建立在我们取得重大进展的基础上，首先是验证 丝虫线虫，进一步扩大了我们的五个具有类似化合物的高优先级支架的名单，通过使用 药效团搜索，随后发现和合理设计创新的成虫线虫- 选择性药物。新合成的化合物将在效力和选择性方面进行优化。 使用系统生物学方法研究寄生虫对宿主以及对同源丝虫线虫靶标的影响。 我们还将确认最有希望的先导化合物的作用模式，并将对其进行评估 我们为便于评估候选药物而开发的两种丝虫病小动物模型的体内疗效 活体内(帕汉氏丝虫/沙鼠和陈氏丝虫/沙鼠)。 整个方法对两个化合物系列进行迭代优化，并在最后 在该项目中，我们计划至少有一种大杀丝杀菌剂候选药物进入晚期临床前阶段 学习。总体而言，该项目将着重解决一个关键的研究，从而解决业务差距； 新型高效、安全的大杀丝虫药物的鉴定与开发。我们的理性发现方法 有可能提供直接杀死成虫的大杀丝虫药物，以实现消除 人类盘尾丝虫病的目标。

Abstract River blindness (onchocerciasis) is a major neglected chronic tropical disease that has been selected by the WHO for elimination by 2030. Currently, international control programs attempt to interrupt transmission of infection with annual mass drug administration (MDA), over the 10-14 years lifetime of the adult worms, using the microfilaricidal drug ivermectin that kills the microfilariae (mf) of Onchocerca volvulus, the causative agent of onchocerciasis. However, MDA with ivermectin is confounded in Africa because it cannot be used in areas co- endemic for loiasis due to the risk of severe adverse events. The overall goal of our project is to develop a novel direct macrofilaricidal (lethal to adult worms directly) preclinical candidate drug as targeted therapy for onchocerciasis using a multidimensional interdisciplinary experimental approach. Our proposal is based on two main resources we have established: a) an extensive omics resource that allowed the identification of defined conserved and diversified essential molecular targets in adult filarial worms, and b) a multifaceted screening funnel that was used successfully to phenotypically screen in vitro a library of drugs approved for clinical use, resulting in the identification of drugs with macrofilaricidal activity. In silico prioritization interfaced with the experimental identification of drugs that were active against the adult stage of filarial nematodes resulted in a short list of inhibitors with known drug-indication and putative target indication pairs that form the basis for our rational optimization of new compounds with direct macrofilaricidal potential. Our proposed aims thus build on our significant progress starting with validating the canonical targets in filarial nematodes, further expanding the list of our five high priority hit scaffolds with similar compounds by using pharmacophore searches, followed by discovery and rational design of innovative adult filarial nematode- selective drugs. The newly synthesized compounds will be optimized for potency and selectivity against the parasites vs. the host as well as against the cognate filarial nematode targets using a systems biology approach. We will also confirm the mode of action for the most promising lead compounds which will also be assessed for in vivo efficacy in two filarial small animal models that we have developed to facilitate assessing drug candidates in vivo (Brugia pahangi/jirds and Onchocerca ochengi/jirds). The overall approach deploys iterative optimization of two chemical series of compounds, and by the end of the project we plan to have at least one macrofilaricidal drug candidate to move into late stage preclinical studies. Overall, this project will emphatically address a critical research and thus operational gap; the identification and development of novel potent and safe macrofilaricidal drugs. Our rational discovery approach has the potential of providing macrofilaricidal drugs that kill directly adult worms needed to achieve the elimination goals for the human onchocerciasis.