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Role of Molecular Recognition in l-Cystine Crystal Growth Inhibition
[Image: see text] 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...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Chemical
Society
2017
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5722434/ https://www.ncbi.nlm.nih.gov/pubmed/29234242 http://dx.doi.org/10.1021/acs.cgd.7b00236 |
Sumario: | [Image: see text] 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 {101̅0} 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. |
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