(217cj) Design of Biomimetic Crystal Modifiers of Calcium Biomineralization As Potential Drug Candidates for Pathological Diseases
Pathological biomineralization is believed to be regulated in vivo by the interaction of urinary constituents with crystal interfaces. Here we examine the role of native and biomimetic growth modifiers of calcium oxalate monohydrate (COM), which is the most prevalent crystalline constituent of human kidney stones. Many proteins and glycosaminoglycans in urine are putative growth inhibitors and display an affinity for binding to specific surfaces of COM crystals to suppress their growth (and aggregation) in vivo. We have examined some of the most common constituents identified by proteomic studies of the organic matrix of human stones. These studies reveal a range of COM crystal inhibitors and promoters. To characterize their efficacy and specificity for binding to COM crystal surfaces, we used a combination of experimental techniques to quantify the effects of these urinary constituents on COM crystal size, habit, surface architecture, and growth kinetics. Results of these studies reveal that certain binary combinations of urinary components exhibit a synergetic enhancement of their efficacy, while other combinations yielded antagonistic effects. Using the most effective urinary proteins as inspiration, we designed and tested small peptides (15 to 20 amino acids) as COM growth modifiers (i.e. biomimetic analogues) . We developed a high-throughput approach to synthesize and screen peptide libraries as a quick and reliable assay to measure their efficacy for inhibiting COM crystallization. Our results show that subtle variations in amino acid sequences and composition have a profound effect on growth inhibition. Collectively, these studies are a basis for ongoing initiatives to design novel drug candidates for kidney stone disease  and a generalized platform for the rational design of inorganic and advanced materials with tailored properties.
 Farmanesh, S., Chung, J., Chandra, D., Sosa, R.D., Karande, P., Rimer, J.D., J. Cryst. Growth (2013) In Press.
 Rimer, J.D., An, Z., Zhu, Z., Lee, M.H., Goldfarb, D.S., Wesson, J.A., Ward, M.D., Science
330 (2010) 337-341.