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Role of Molecular Recognition in l-Cystine Crystal Growth Inhibition.


ABSTRACT: l-Cystine kidney stones-aggregates of single crystals of the hexagonal form of l-cystine-afflict more than 20?000 individuals in the United States alone. Current therapies are often ineffective and produce adverse side effects. Recognizing that the growth of l-cystine crystals is a critical step in stone pathogenesis, real-time in situ atomic force microscopy of growth on the (0001) face of l-cystine crystals and measurements of crystal growth anisotropy were performed in the presence of prospective inhibitors drawn from a 31-member library. The most effective molecular imposters for crystal growth inhibition were l-cystine mimics (aka molecular imposters), particularly l-cystine diesters and diamides, for which a kinetic analysis revealed a common inhibition mechanism consistent with Cabrera-Vermilyea step pinning. The amount of inhibitor incorporated by l-cystine crystals, estimated from kinetic data, suggests that imposter binding to the {0001} face is less probable than binding of l-cystine solute molecules, whereas imposter binding to {101?0} faces is comparable to that of l-cystine molecules. These estimates were corroborated by computational binding energies. Collectively, these findings identify the key structural factors responsible for molecular recognition between molecular imposters and l-cystine crystal kink sites, and the inhibition of crystal growth. The observations are consistent with the reduction of l-cystine stone burden in mouse models by the more effective inhibitors, thereby articulating a strategy for stone prevention based on molecular design.

SUBMITTER: Poloni LN 

PROVIDER: S-EPMC5722434 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Role of Molecular Recognition in l-Cystine Crystal Growth Inhibition.

Poloni Laura N LN   Zhu Zina Z   Garcia-Vázquez Nelson N   Yu Anthony C AC   Connors David M DM   Hu Longqin L   Sahota Amrik A   Ward Michael D MD   Shtukenberg Alexander G AG  

Crystal growth & design 20170413 5


l-Cystine kidney stones-aggregates of single crystals of the hexagonal form of l-cystine-afflict more than 20 000 individuals in the United States alone. Current therapies are often ineffective and produce adverse side effects. Recognizing that the growth of l-cystine crystals is a critical step in stone pathogenesis, real-time in situ atomic force microscopy of growth on the (0001) face of l-cystine crystals and measurements of crystal growth anisotropy were performed in the presence of prospec  ...[more]

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