Calcium oxalate (CaOx) crystal-induced nephropathies comprise a range of kidney disorders, for which there are no efficient pharmacological treatments. Although CaOx crystallization inhibitors have been suggested as a therapeutic modality already decades ago, limited progress has been made in the discovery of potent molecules with efficacy in animal disease models. Herein, an image-based machine learning approach to systematically screen chemically modified myo-inositol hexakisphosphate (IP6) analogues is utilized, which enables the identification of a highly active divalent inositol phosphate molecule. To date, this is the first molecule shown to completely inhibit the crystallization process in the nanomolar range, reduce crystal-cell interactions, thereby preventing CaOx-induced transcriptomic changes, and decrease renal CaOx deposition and kidney injury in a mouse model of hyperoxaluria. In conclusion, IP6 analogues based on such a scaffold may represent a new treatment option for CaOx nephropathies.

中文翻译：

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草酸钙结晶抑制剂，用于治疗草酸肾病。

草酸钙（CaOx）晶体引起的肾病包括一系列肾脏疾病，目前尚无有效的药物治疗方法。尽管几十年前就已经提出将CaOx结晶抑制剂作为一种治疗手段，但是在动物疾病模型中发现具有效力的有效分子的研究进展有限。在本文中，利用基于图像的机器学习方法来系统地筛选化学修饰的肌醇六磷酸（IP6）类似物，从而能够鉴定出高活性的二价肌醇磷酸分子。迄今为止，这是第一个在纳摩尔范围内完全抑制结晶过程，减少晶胞相互作用从而阻止CaOx诱导的转录组变化的分子，并减少高草酸尿小鼠模型中的肾脏CaOx沉积和肾脏损伤。总之，基于这种支架的IP6类似物可能代表CaOx肾病的新治疗选择。