Kletzmayr Anna, Bigler Melina, Montanari Elita, Kuro-O Makoto, Hayashi Hirosaka, Ivarsson Mattias E, Leroux Jean-Christophe
Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zurich, 8093 Zurich, Switzerland.
Division of Anti-aging Medicine, Center for Molecular Medicine, Jichi Medical University 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, Japan.
ACS Pharmacol Transl Sci. 2020 Nov 23;3(6):1339-1351. doi: 10.1021/acsptsci.0c00153. eCollection 2020 Dec 11.
Kidney calcification increases the risk of chronic kidney disease. However, to date, renal calcium phosphate crystallization, a main initiating and driving factor of kidney calcification, has not been explored as a drug target. Pre-clinical drug development is hampered by limited knowledge on the broad range of kidney calcification disorders, characterized by a multifactorial process of disease progression. In this work, we first established an calcification profiling platform to accelerate pre-clinical drug discovery. The image-based profiling assay allowed the rapid testing of several ionic stimuli and/or inhibitory molecules. We then leveraged a previously established library of inositol hexakisphosphate analogues to identify a renal calcium phosphate inhibitor. A lead compound showed and efficacy to prevent calcium phosphate-induced kidney damage. In conclusion, this work reports a renal calcium phosphate inhibitor that could efficiently reduce kidney damage and emphasizes the utility and translational value of the calcification platform.
肾钙化会增加患慢性肾病的风险。然而，迄今为止，作为肾钙化的主要起始和驱动因素的肾磷酸钙结晶尚未被作为药物靶点进行研究。由于对以疾病进展的多因素过程为特征的广泛肾钙化疾病的了解有限，临床前药物开发受到阻碍。在这项工作中，我们首先建立了一个钙化分析平台，以加速临床前药物发现。基于图像的分析测定允许快速测试几种离子刺激物和/或抑制分子。然后，我们利用先前建立的肌醇六磷酸类似物库来鉴定一种肾磷酸钙抑制剂。一种先导化合物显示出预防磷酸钙诱导的肾损伤的效力和效果。总之，这项工作报道了一种能有效减少肾损伤的肾磷酸钙抑制剂，并强调了钙化平台的实用性和转化价值。
