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

摘要 河盲症（盘尾丝虫病）是一种被忽视的主要慢性热带疾病， 世卫组织承诺到2030年消除。目前，国际控制计划试图中断 感染与每年大规模药物管理（MDA），超过10-14年的寿命的蠕虫，使用 一种杀微丝蚴的药物伊维菌素，能杀死盘尾丝虫的微丝蚴（mf），盘尾丝虫是引起 盘尾丝虫病然而，MDA与伊维菌素在非洲是混淆的，因为它不能用于共同的地区， 由于存在严重不良事件的风险，洛伐他汀是地方性的。我们项目的总体目标是开发一部小说 直接杀大型丝虫（直接对蠕虫）的临床前候选药物，作为 盘尾丝虫病使用多维跨学科的实验方法。 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， 允许鉴定成年蠕虫中确定的保守和多样化的必需分子靶标， 和B）多面筛选漏斗，其成功地用于体外表型筛选 批准用于临床的药物，从而鉴定出具有杀微丝蚴活性的药物。计算机模拟 优先顺序与对成年阶段的药物有活性的实验鉴定相结合， 丝虫导致了一个简短的抑制剂清单，具有已知的药物适应症和推定的靶向适应症 这些对构成了我们合理优化具有直接杀大型丝虫潜力的新化合物的基础。 因此，我们提出的目标建立在我们从验证规范目标开始的重大进展基础上， 丝虫线虫，进一步扩大了我们的五个高优先级击中支架与类似的化合物，通过使用 药效团搜索，然后发现和合理设计创新的成年丝虫线虫- 选择性药物新合成的化合物将被优化用于针对药物的效力和选择性。 寄生虫对宿主以及对同源丝虫线虫靶标的系统生物学方法。 我们还将确认最有希望的先导化合物的作用方式，并对其进行评估。 在我们开发的两种丝虫小动物模型中的体内功效，以便于评估候选药物 体内（Brugia pahangi/沙鼠和Onchocerca ochengi/沙鼠）。 整体方法部署了两个化学系列化合物的迭代优化，并在最后 在该项目中，我们计划至少有一种杀微丝蚴候选药物进入临床前后期阶段 问题研究总的来说，该项目将着重解决一个关键的研究，从而业务差距; 鉴定和开发新的有效和安全的杀微丝蚴药物。我们的理性发现方法 有可能提供直接杀死蠕虫以实现消除所需的杀微丝蚴药物 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.