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Inhibitors of Calcium Oxalate Crystallization for the Treatment of Oxalate Nephropathies.

  • Kletzmayr A Institute of Pharmaceutical Sciences Department of Chemistry and Applied Biosciences ETH Zurich 8093 Zurich Switzerland.
  • Mulay SR Division of Nephrology Department of Medicine IV University Hospital LMU Munich 80336 Munich Germany.
  • Motrapu M Division of Nephrology Department of Medicine IV University Hospital LMU Munich 80336 Munich Germany.
  • Luo Z Institute of Pharmaceutical Sciences Department of Chemistry and Applied Biosciences ETH Zurich 8093 Zurich Switzerland.
  • Anders HJ Division of Nephrology Department of Medicine IV University Hospital LMU Munich 80336 Munich Germany.
  • Ivarsson ME Inositec Inc. 8005 Zurich Switzerland.
  • Leroux JC Institute of Pharmaceutical Sciences Department of Chemistry and Applied Biosciences ETH Zurich 8093 Zurich Switzerland.
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  • 2020-04-25
Published in:
  • Advanced science (Weinheim, Baden-Wurttemberg, Germany). - 2020
calcium oxalate crystallization inhibitors
chronic kidney disease
image‐based drug screening
kidney calcification
kidney stones
English 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.
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  • English
Open access status
gold
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https://sonar.ch/global/documents/244274
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