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 {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.

Design, synthesis, and evaluation of l-cystine diamides as l-cystine crystallization inhibitors for cystinuria

“…The Bravais-Friedel Donnay-Harker (BFDH) calculated platelet morphology (data not shown) agrees well with the experimentally observed morphology. 8, 14 The BFDH approach does not consider solvent effect; the fact that the computed morphology (with no solvent present) agrees with the experimentally observed in the presence of solvent (water) points to a strong inter-molecular interaction between the L-cystine molecules, which makes the L-cystine-water molecular interaction obscured in the L-cystine crystal morphology development. This is different from cases where intermolecular interactions inside the crystal is relatively weak compared to surface-solvent interactions.…”

Stimuli-responsive temporary adhesives: enabling debonding on demand through strategic molecular design

“…266 Similarly, researchers have begun studying the impact of chemical and physical defects in determining mechanical properties. [267][268][269][270][271][272][273][274][275] These efforts should be continued and expanded upon. Future inspiration for adhesive characterization techniques can be adapted from standard industry test methods (e.g., ASTM or TAPPI procedures) commonly applied in other elds of materials characterization.…”

Cystinuria and cystinosis are usually related to L-cystine: is this really the case for cystinosis? A physicochemical investigation at micrometre and nanometre scale

“…The structural characterisation of cystine kidney stones has been discussed in several publications. Consistent with its crystallographic structure (hexagonal crystal system, P6 1 22 space group), all the papers on synthetic [47][48][49][50][51][52][53][54] or biological [18][19][20][21]24,55,56,[64][65][66] cystine have reported a hexagonal morphology. On SEM observations, at the micrometre scale, we can clearly see the hexagonal shape of the cystine deposits in kidney stones from mice and humans affected by cystinuria (Figure 2).…”

“…The literature clearly indicates the presence of rectangular crystals made of cystine [29][30][31][71][72][73][74][75][76][77][78][79]81]. Such morphology is not expected for cystine crystals which are typically hexagonal for synthetic [47][48][49][50][51][52][53][54] as well as for biological [18][19][20][21]24,55,56,[64][65][66] samples. Rectangular-like crystallites are observed in the case of synthetic cysteine (Figure 5c).…”

“…To do this, we undertook a structural and spectroscopic analysis of such abnormal deposits using scanning electron microscopy (SEM) [14,39,40], µFTIR (Fourier Transform InfraRed) [14,41,42], AFM-IR (atomic force microscopy coupled with IR) spectroscopy [43,44] and OPTIR (Optical Photothermal IR) spectroscopy [45,46]. SEM offers the opportunity to directly observe the morphology and size of crystallites at the micrometre scale and contributes significantly to the structural description of cystine crystals (see for examples [47][48][49][50][51][52][53][54]). µFTIR spectroscopy constitutes the gold standard for precisely determining the chemical composition of kidney stones [41,42,55,56].…”