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

加速丝虫药物研发以治疗河盲症的综合方法

基本信息

批准号：
10317958
负责人：
James W Janetka
金额：
$ 41万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-30 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10317958
关键词：
Address Adult Affect Africa Animal Model Area Aspartic Endopeptidases Autopsy Bioavailable Biochemical Biological Assay Brugia pahangi Cell Line Chemicals Chronic Chronic Disease Clinical Complement Developing Countries Development Disease Docking Drug Targeting Encephalopathies Evaluation Evaluation Studies Female Fertility Filariasis G-Protein-Coupled Receptors Genetic Transcription Goals Homology Modeling Human In Vitro Individual Infection International Interruption Intervention Intestinal Volvulus Ivermectin Jird Knowledge Lead Libraries Ligands Loa Loa loa Loiasis Modeling Molecular Molecular Target Nematoda Ocular Onchocerciasis Onchocerca Onchocerca volvulus Onchocerciasis Oral Organizational Objectives Orthologous Gene Outcome Parasites Pharmaceutical Preparations Phenotype Pimozide Population Property Protease Inhibitor RNA Interference Recombinant Proteins Research Resources Risk Ritonavir Rodent Rodent Model Schedule Selection Criteria Series Serious Adverse Event Structure Systems Biology Testing Therapeutic Toxic effect Tropical Disease Validation Visually Impaired Persons World Health Organization analog base blind cell motility design drug candidate drug discovery drug use screening efficacy validation in silico in vivo in vivo evaluation inhibitor/antagonist innovation interdisciplinary approach knock-down lead candidate lead optimization meetings metabolomics multidisciplinary neglect novel novel therapeutics pharmacophore pre-clinical preclinical evaluation preclinical study process optimization programs response scaffold screening targeted treatment transcriptome sequencing transcriptomics transmission process

项目摘要

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.

抽象的河盲症（盘尾丝虫病）是一种被忽视的主要慢性热带疾病，已被世界卫生组织 (WHO) 计划到 2030 年消除该病毒。目前，国际控制计划试图阻止病毒传播在成虫的 10-14 年寿命期间，每年进行大规模药物管理 (MDA) 感染，使用杀微丝蚴药物伊维菌素，可杀死盘尾丝虫的微丝蚴（MF），盘尾丝虫是盘尾丝虫的病原体盘尾丝虫病。然而，MDA 与伊维菌素在非洲却令人困惑，因为它不能在共同使用的地区使用。由于存在严重不良事件的风险，罗阿西斯流行。我们项目的总体目标是开发一种新颖的直接杀灭巨丝虫（直接杀死成虫）的临床前候选药物作为靶向治疗盘尾丝虫病采用多维跨学科实验方法。我们的提案基于我们已建立的两个主要资源：a) 广泛的组学资源，允许鉴定成虫丝虫中明确的保守且多样化的基本分子靶标， b) 多层面筛选漏斗，已成功用于体外表型筛选批准用于临床的药物，从而鉴定出具有杀丝虫活性的药物。计算机模拟优先顺序与对成人阶段有效的药物的实验鉴定相结合丝虫线虫产生了一份简短的抑制剂清单，这些抑制剂具有已知的药物适应症和假定的目标适应症这些对构成了我们合理优化具有直接杀灭大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的基础上丝虫线虫，通过使用类似化合物进一步扩大了我们的五个高优先级命中支架的列表药效团搜索，然后发现和合理设计创新的成虫丝虫线虫选择性药物。新合成的化合物将针对效力和选择性进行优化使用系统生物学方法对抗宿主以及同源丝虫线虫目标的寄生虫。我们还将确认最有前途的先导化合物的作用方式，这些化合物也将被评估我们开发的两种丝虫小动物模型的体内疗效，以方便评估候选药物体内（Brugia pahangi/jirds 和 Onchocerca o Chengi/jirds）。整体方法部署了两种化学系列化合物的迭代优化，最后在该项目中，我们计划至少有一种杀大丝虫候选药物进入后期临床前阶段研究。总体而言，该项目将重点解决关键研究以及操作方面的差距；这新型有效且安全的杀丝虫药物的鉴定和开发。我们的理性发现方法有潜力提供杀巨丝虫药物，直接杀死实现消除所需的成虫人类盘尾丝虫病的目标。