Drosophila melanogaster as a function-based high-throughput screening model for antinephrolithiasis agents in kidney stone patients
Drosophila melanogaster as a function-based high-throughput screening model for antinephrolithiasis agents in kidney stone patients
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DOI：
10.1242/dmm.035873
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发表时间：
2018-11-01
影响因子：
4.3
通讯作者：
Leong, Hon S.
中科院分区：
文献类型：
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作者：
Ali, Sohrab N.;Dayarathna, Thamara K.;Leong, Hon S.
肾结石疾病涉及结石形成盐的聚集，这是尿液中溶质过饱和的结果。由于缺乏适合药物筛选的实用临床前模型，这种主要是代谢和生化疾病的新型治疗药物的开发受到阻碍。在这里，黑腹果蝇，一个新兴的模型肾结石疾病的研究，被改编为一个高通量的功能性药物筛选平台，独立于哺乳动物肾结石的多因素性质。通过功能筛选，一种新的化合物，通常被称为熊果苷，特异性结合草酸盐，肾结石的关键组成部分的治疗潜力，被确定。通过等温滴定量热法，高效液相色谱和原子力显微镜，熊果苷被确定为与钙和草酸在自由和结合状态，破坏晶格结构，生长和结晶。当用于处理患者尿样时，熊果苷显着消除体内结石形成，并在低pH值尿液条件下优于柠檬酸钾，这是由于其以尿酸盐为中心的作用模式。这一新的抗结石化合物是通过D. melanogaster，独立于哺乳动物模型，为这个平台带来了更大的认可，代谢特征是主要结果，强调了D.在类似疾病中作为高通量药物筛选平台。这是第一次描述D. melanogaster作为高通量化学文库筛选的模型系统。
Kidney stone disease involves the aggregation of stone-forming salts consequent to solute supersaturation in urine. The development of novel therapeutic agents for this predominantly metabolic and biochemical disorder have been hampered by the lack of a practical pre-clinical model amenable to drug screening. Here, Drosophila melanogaster, an emerging model for kidney stone disease research, was adapted as a high-throughput functional drug screening platform independent of the multifactorial nature of mammalian nephrolithiasis. Through functional screening, the therapeutic potential of a novel compound commonly known as arbutin that specifically binds to oxalate, a key component of kidney calculi, was identified. Through isothermal titration calorimetry, high-performance liquid chromatography and atomic force microscopy, arbutin was determined to interact with calcium and oxalate in both free and bound states, disrupting crystal lattice structure, growth and crystallization. When used to treat patient urine samples, arbutin significantly abrogated calculus formation in vivo and outperformed potassium citrate in low pH urine conditions, owing to its oxalate-centric mode of action. The discovery of this novel antilithogenic compound via D. melanogaster, independent of a mammalian model, brings greater recognition to this platform, for which metabolic features are primary outcomes, underscoring the power of D. melanogaster as a high throughput drug screening platform in similar disorders. This is the first description of the use of D. melanogaster as the model system for a high-throughput chemical library screen.