Inhibitors of Calcium Oxalate Crystallization for the Treatment of Oxalate Nephropathies

Abstract

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.

Investigational Therapies for Primary Hyperoxaluria

“…Crystals further trigger epithelial cell injury and inflammation . Adapted from ref under the terms of the Creative Commons Attribution License.…”

“…Furthermore, the molecule also reduced binding of CaOx crystals to renal epithelial cells, suggesting a dual mode of action. Importantly, in a mouse model of hyperoxaluria, wherein renal CaOx deposition and tissue injury was induced by an oxalate enriched and calcium depleted diet, both CaOx deposition and kidney damage were reduced and kidney function enhanced by OEG 4 -(IP5) 2 . This study was the first to bridge the gap between in vitro and in vivo studies, demonstrating and integrating the effect a crystallization inhibitor on several aspects of the pathophysiology, namely, crystal nucleation and growth, crystal adhesion to renal epithelial cells, and crystal-induced cellular injury.…”

“…Addition of the inhibitor stabilizes early stage nanoparticles, thereby delaying crystallization over the timecourse of hours. With increasing concentrations of inhibitor, the delayed crystallization of CO is favored over COM . Reprinted from ref under the terms of the Creative Commons Attribution License.…”

“…With increasing concentrations of inhibitor, the delayed crystallization of CO is favored over COM . Reprinted from ref under the terms of the Creative Commons Attribution License.…”

Small Molecule-Based Enzyme Inhibitors in the Treatment of Primary Hyperoxalurias

“…Inhibition of CaOx crystallization is another strategy under research aimed at the elimination of the renal damage caused by crystal deposition [ 75 , 76 , 77 ]. In this sense, important advances have been made recently, with the discovery of a new powerful class of CaOx inhibitors based in multivalent inositol phosphate molecules that can inhibit the crystallization process as well as the CaOx-cell interactions that lead to kidney damage [ 78 ].…”