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：
10478172
负责人：
James W Janetka
金额：
$ 39.77万
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/10478172
关键词：
Address Adult Affect Africa Animal Model Area Aspartic Endopeptidases Autopsy 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 Persons 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 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 rational design 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.

抽象的河流失明（Onchocerciasis）是一种主要被忽视的慢性热带疾病，已被谁在2030年之前取消。目前，国际控制计划试图中断年度大众药物管理局（MDA）感染成人蠕虫的10 - 14年，使用杀死OnChocerca volvulus的微丝菌（MF）的微椰子药伊维菌素，尾cer虫。但是，非洲的MDA与伊维菌素混淆，因为它不能用于共同的领域由于发生严重的不良事件的风险，因此岩石症特有。我们项目的总体目标是开发小说直接大写（直接致死对成年蠕虫致死）临床前候选药物作为针对性的治疗使用多维跨学科实验方法进行尾尾c。我们的建议基于我们建立的两个主要资源：a）广泛的OMICS资源允许鉴定成人丝状蠕虫中定义的保守和多样化的基本分子靶标， b）多方面的筛选漏斗成功地用于表型在体外筛选一个库批准用于临床用途的药物，导致鉴定出具有大写活性的药物。在计算机中优先考虑与对成人阶段活跃的药物的实验鉴定有关丝状线虫导致了已知药物指示和推定目标指示的抑制剂的简短列表对我们合理优化具有直接大写潜力的新化合物的基础的对。因此，我们提出的目标是基于我们的重大进展，从验证规范目标开始丝状线虫，通过使用类似化合物的五个高优先级脚手架的列表进一步扩展药效团搜索，然后发现和合理设计创新的成人丝状线虫 - 选择性药物。新合成的化合物将被优化，以实现效力和选择性寄生虫与宿主以及使用系统生物学方法的同源性丝状线虫目标。我们还将确认最有前途的铅化合物的行动方式，该化合物也将进行评估我们已经开发出促进候选药物的两个丝状小动物模型的体内功效 in Vivo（Brugia Pahangi/Jirds和Onchocerca Ochengi/Jirds）。总体方法部署了两个化学系列化合物的迭代优化，最后在该项目中，我们计划至少有一名大脂肪药物候选者进入晚期临床前研究。总体而言，该项目将强调解决一项重要的研究，从而解决差距。这鉴定和开发新型有效和安全的大写药物。我们的理性发现方法有可能提供杀死消除需要直接杀死成人蠕虫的大写药物人类尾c的目标。