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2017 ; 40
(4
): 555-567
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Cysteamine revisited: repair of arginine to cysteine mutations
#MMPMID28643139
Gallego-Villar L
; Hannibal L
; Häberle J
; Thöny B
; Ben-Omran T
; Nasrallah GK
; Dewik AN
; Kruger WD
; Blom HJ
J Inherit Metab Dis
2017[Jul]; 40
(4
): 555-567
PMID28643139
show ga
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, in general, Arg to Cys
changes comprise about 8% of missense mutations, repair of this specific mutation
may provide promising avenues for many genetic diseases.
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