Cystine growth inhibition through molecular mimicry: a new paradigm for the prevention of crystal diseases

Abstract

Cystinuria is a genetic disease marked by recurrent kidney stone formation, usually at a young age. It frequently leads to chronic kidney disease. Treatment options for cystinuria have been limited despite comprehensive understanding of its genetic pathophysiology. Currently available therapies suffer from either poor clinical adherence to the regimen or potentially serious adverse effects. Recently, we employed atomic force miscopy (AFM) to identify L-cystine dimethylester (CDME) as an effective molecular imposter of L-cystine, capable of inhibiting crystal growth in vitro. More recently, we demonstrated CDME's efficacy in inhibiting L-cystine crystal growth in vivo utilizing a murine model of cystinuria. The application of AFM to discover inhibitors of crystal growth through structural mimicry suggests a novel approach to preventing and treating crystal diseases.

Fig. 1

a, b Real-time in situ AFM images of a l-cystine crystal, acquired 12 min apart. A pair of hexagonal hillocks generated by two closely spaced dislocations serves as landmarks. c, d AFM images of a single dislocation center of c l-cystine and d d-cystine crystal during growth. e, f AFM image of a hexagonal growth hillock on the (001) face of l-cystine before and after the addition of l-CDME (5 mg/L; 0.02 mM), revealing roughening of the {100} steps due to step pinning. Images were acquired in aqueous solutions containing 2 mM l-cystine. Reproduced with permission from Science

Fig. 2

Bladder stones recovered from two water-fed (left) and three CDME-fed (right, 10 mg/mL daily for 4 weeks) knockout male mice. The stones recovered from CDME-fed mice are more numerous in number and smaller in size compared to those of water-fed mice