(543d) Tailoring Inhibitors of Pathological Crystallization: New Platforms for Drug Design

Pathological mineralization arises from the precipitation of inorganic and organic constituents in the human body. Their occurrence is driven by supersaturated environments where dissolved solute undergoes a phase transformation from solution via processes consisting of nucleation, growth, aggregation and retention on tissues. One such physiological disorder is kidney stone formation, primarily composed of calcium salts and other minor constituents. About 80% of kidney stones are composed of calcium oxalate monohydrate (COM).¹ The current therapy is citrate supplementation to reduce stone growth; however, stone recurrence remains a concern for patients and clinicians, thereby stressing the need for alternative therapies. In order to address this issue, we have investigated a series of crystal growth inhibitors, which are molecules that adsorb on crystals and block solute incorporation.^2-3 Inhibitors have different modes of action to suppress crystal growth, knowledge of which is integral to the design of effective drugs.

Here, we present the results of bulk, kinetic, and interfacial studies of COM growth inhibition. We identify modifiers with binding specificity to COM crystal surfaces,^4-5 leading to either the inhibition or promotion of growth. Modifier interactions with crystal surfaces are instigated using in situ atomic force microscopy (AFM) to capture dynamic events with sufficient spatiotemporal resolution. AFM reveals unique modes of actions for different modifiers; and from these studies we assess modifier efficacy as a platform to design therapeutics for pathological crystallization.

1. Wesson, J. A.; Ward, M. D., Pathological Biomineralization of Kidney Stones. Elements 2007, 3 (6), 415-421.

2. Alamani, B. G., Rimer, J. D., Molecular modifiers of kidney stones. Curr Opin Nephrol Hy 2017.

3. Olafson, K. N.; Li, R.; Alamani, B. G.; Rirner, J. D., Engineering Crystal Modifiers: Bridging Classical and Nonclassical Crystallization. Chemistry of Materials 2016, 28 (23), 8453-8465.

4. Chung, J.; Granja, I.; Taylor, M. G.; Mpourmpakis, G.; Asplin, J. R.; Rimer, J. D., Molecular modifiers reveal a mechanism of pathological crystal growth inhibition. Nature 2016, 536 (7617), 446-450.

5. Farmanesh, S.; Alamani, B. G.; Rimer, J. D., Identifying alkali metal inhibitors of crystal growth: a selection criterion based on ion pair hydration energy. Chemical Communications 2015, 51 (73), 13964-13967.