Cysteamine revisited: repair of arginine to cysteine mutations

Abstract

Cysteamine is a small aminothiol endogenously derived from coenzyme A degradation. For some decades, synthetic cysteamine has been employed for the treatment of cystinosis, and new uses of the drug continue to emerge. In this review, we discuss the role of cysteamine in cellular and extracellular homeostasis and focus on the potential use of aminothiols to reconstitute the function of proteins harboring arginine (Arg) to cysteine (Cys) mutations, via repair of the Cys residue into a moiety that introduces an amino group, as seen in basic amino acid residues Lys and Arg. Cysteamine has been utilized in vitro and ex vivo in four different genetic disorders, and thus provides “proof of principle” that aminothiols can modify Cys residues. Other aminothiols such as mercaptoethylguanidine (MEG) with closer structural resemblance to the guanidinium moiety of Arg are under examination for their predicted enhanced capacity to reconstitute loss of function. Although the use of aminothiols holds clinical potential, more studies are required to refine specificity and treatment design. The efficacy of aminothiols to target proteins may vary substantially depending on their specific extracellular and intracellular locations. Redox potential, pH and specific aminothiol abundance in each physiological compartment are expected to influence the reactivity and turnover of cysteamine and analogous drugs. Upcoming research will require the use of suitable cell and animal models featuring Arg to Cys mutations. Since Arg to Cys changes comprise in general about 8% of missense mutations, repair of this specific mutation may provide promising avenues for many genetic diseases.

Challenges for cysteamine stabilization, quantification, and biological effects improvement

“…The degradation of CoA leads to the formation of pantetheine, which is hydrolyzed by pantetheinase to obtain cys and pantothenic acid ( Fig. 3 ) [ 23 , 24 ]. Then, the oxidation of cys by cys dioxygenase produces hypotaurine.…”

“…10 ). Many reviews have profoundly discussed these applications [ 7 , 23 , 24 ]. We will focus on the main applications of cys as a radioprotective agent, in the treatment of cystinosis, and for anti-tumor proliferation.…”

The Spectrum of Mutations of Homocystinuria in the MENA Region

“…Other potential chemical chaperones include tauroursodeoxycholic acid (TUDCA), sodium 4-phenylbutyrate (PBA), urea derivatives chemical chaperones such as trimethylamine oxide (TMAO), amino acid derivatives chemical chaperones such as glycine, polyols chemical chaperones such as glycerol and sorbitol, mannitol, maltose, phenyl butyric acid. Additionally, the use of aminothiols, such as cysteamine, holds potential clinical promise to target arginine to cysteine mutations of different genetic disorders [88]. It is worth mentioning that SAM analogs are also considered pharmacological chaperones and kinetic stabilizers that could prevent the misfolding and rapid degradation of mutant CBS protein [89].…”

Chemistry and Biochemistry of Sulfur Natural Compounds: Key Intermediates of Metabolism and Redox Biology

“…This aminothiol has been proposed to repair Arg to Cys missense mutations in genetic disorders. Upon binding of cysteamine to the Cys residue by a disulfide bond, a mimic structure resembling the original arginine residue is created on the mutated protein [ 144 ].…”