(83e) Crystal Growth Inhibitors for the Prevention of L-Cystine Kidney Stones through Molecular Design

L-cystine kidney stone disease is a debilitating genetic disorder that affects more than 20,000 U.S. citizens ¹ and is more likely to cause chronic kidney disease than the most widespread stone constituent, calcium oxalate monohydrate (COM) ^2-4. The formation of L-cystine stones is a consequence of excessive levels of L-cystine in the urine due to defective reabsorption of filtered cystine, which in turn is associated with an autosomal recessive disorder caused by mutations in one of the two genes which code for components of proximal renal tubule amino acid transporters. This condition is exacerbated by the low solubility of L-cystine, which favors facile formation of crystals that aggregate into stones. Current treatments for L-cystine stone prevention include dilution through high fluid intake, increasing urine pH through ingestion of alkalinizing potassium or sodium salts, or the administration of L-cystine binding thiol drugs (CBTDs), which react with L-cystine to generate more soluble asymmetric disulfides. These treatments suppress, but typically do not completely prevent, stone formation, while CBTDs can cause adverse side effects (e.g. nausea, fever, and skin allergies). Here we will present an alternative approach to the prevention of L-cystine kidney stones based on crystal growth inhibition achieved through the tailored growth inhibitors L-cystine dimethyl ester (L-CDME) and L-cystine methyl ester (L-CME) ? structural mimics of L-cystine ? which exhibit molecular recognition for binding to specific crystal surfaces ⁵. Real-time in situ atomic force microscopy reveals that L-CDME and L-CME dramatically reduce the growth velocity of surface steps emanating from well-defined hexagonal spiral dislocations due to specific binding of these inhibitors at step sites, thereby frustrating the attachment of L-cystine solute molecules. The AFM observations at the near-molecular level mirror macroscopic phenomena of reduced crystal yield and crystal size in the presence of L-CDME and L-CME, collectively suggesting a new pathway to the prevention of L-cystine stones through molecular design of crystal growth inhibitors.

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[2] Sheng, X., Jung, T., Wesson, J.A., Ward, M.D., PNAS 102 (2005) 267-272

[3] Wesson, J.A. and Ward, M.D., Elements 3 (2007) 415-421

[4] Viswanathan, P., Rimer, J.D., Beshensky, A.M., Zachowicz, W.J., Ward, M.D., Kleinman, J.G., Wesson, J.A., ?Calcium oxalate monohydrate aggregation induced by aggregation of desialylated Tamm-Horsfall protein? Submitted

[5] Rimer, J.D., An, Z., Zhu, Z., Lee, M.H., Wesson, J.A., Goldfarb, D.S., Ward, M.D., ?Crystal growth inhibitors for the prevention of L-cystine kidney stones through molecular design? Submitted