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

Anna KletzmayrShrikant R MulayManga MotrapuZhi LuoHans-Joachim AndersMattias E IvarssonJean-Christophe Leroux
Published in: Advanced science (Weinheim, Baden-Wurttemberg, Germany) (2020)
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.
Keyphrases
  • machine learning
  • mouse model
  • high glucose
  • high throughput
  • single cell
  • diabetic rats
  • deep learning
  • drug induced
  • combination therapy
  • oxidative stress